StemCell Therapy

Experience Normande genetics

Another breeding season is here, along with a new opportunity to experience Normande genetics. Please take a look at our Fall 2016proofsand, if it's your first time, take a leap of faith! Whether you graze or not, crossing with Normande offers many benefits. Check our the various pages of our website for more details about the breed's many strong qualities. See more information on ourcatalog pageon how to choose our bulls. As usual, graziers are advised to focus on bulls with low stature indexes for medium size cows if they cross with Holsteins. Low stature is less important if you cross with Jerseys. Finally, do not forget to follow us on Facebook and Twitter for quicker and more frequent news updates.

Normande Genetics was created in 1997 to bring the top dairy genetics of the Normande breed to the American dairyland. Because the U.S. dairy industry had long since cut its grass roots in favor of intensive, high-energy, grain-based systems, we believed that genetics here were no longer well suited to grass-based operations. That insight has been confirmed consistently in interactions with American dairy farmers, whose herds are suffering loss of functionality in fertility and longevity, owing to over-selection for productivity, and secondarily, dairyness.

Originally focused on grazing daires, we quickly realize that the need for different genetics applies to all dairies, and includes conventional ones. Intensive operations are increasingly faced with fertility and health issues, and many of these issues can be attributed to frail genetics or inbreeding.

While the U.S. dairy sire selection process has started to move towards improving functional traits, it will take time to see results in the field. In addition, in-breeding and a narrowing gene pool for most dairy breeds worldwide add to the problem, so there is no easy and short-term answer to the weakening of health traits.

Thats why crossbreeding makes sense. After all, dairy farmers want to lower their cost of operation while increasing their revenue, which means profits and margins replace production as the main benchmarks of success. In turn, genetic traits that contribute to the bottom line become essential, while selecting for milk production becomes relatively less important. For more information about why crossbreeding is a useful tool, you can download this article:

download "Why Crossbreeding?" Article (PDF)

The Normandes traits serve the objectives of both grass-based and conventional operations in two ways: bringing strength and functionality while adding value whenever possible. The Normande has outstanding attributes as a purebred or in a cross-breeding program. The breed has shown successful examples with all U.S. dairy breeds and is often included in three-way crossbreeding programs. The University of Minnesotas new experimental organic herd includes such a cross.

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normande genetics: sustainable genetics that breed quality

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Supercourse: Epidemiology, the Internet, and Global Health

Ageing, also spelled aging, is the process of becoming older. In the narrow sense, the term refers to biological ageing, especially of human beings and many animals (whereas for example bacteria, perennial plants and some simple animals are potentially immortal). In the broader sense, ageing can refer to single cells within an organism which have ceased dividing (cellular senescence) or to the population of a species (population ageing).

In humans, ageing represents the accumulation of changes in a human being over time,[1] encompassing physical, psychological, and social change. Reaction time, for example, may slow with age, while knowledge of world events and wisdom may expand. Ageing is among the greatest known risk factors for most human diseases:[2] of the roughly 150,000 people who die each day across the globe, about two thirds die from age-related causes.

The causes of ageing are unknown; current theories are assigned to the damage concept, whereby the accumulation of damage (such as DNA breaks or oxidised bases) may cause biological systems to fail, or to the programmed ageing concept, whereby internal processes (such as DNA telomere shortening) may cause ageing.

The discovery, in 1934, that calorie restriction can extend lifespan by 50% in rats has motivated research into delaying and preventing ageing.

Human beings and members of other species, especially animals, necessarily experience ageing and mortality. In contrast, many species can be considered immortal: for example, bacteria fission to produce daughter cells, strawberry plants grow runners to produce clones of themselves, and animals in the genus Hydra have a regenerative ability with which they avoid dying of old age.

Even within humans and other mortal species, there are arguably cells with the potential for immortality: cancer cells which have lost the ability to die when maintained in cell culture such as the HeLa cell line, and specific stem cells such as germ cells (producing ova and spermatozoa).[3] In artificial cloning, adult cells can be rejuvenated back to embryonic status and then used to grow a new tissue or animal without ageing.[4] Normal human cells however die after about 50 cell divisions in laboratory culture (the Hayflick Limit, discovered by Leonard Hayflick in 1961).

After a period of near perfect renewal (in humans, between 20 and 35 years of age), ageing is characterised by the declining ability to respond to stress, increasing homeostatic imbalance and the increased risk of disease. This currently irreversible series of changes inevitably ends in death.

A number of characteristic ageing symptoms are experienced by a majority or by a significant proportion of humans during their lifetimes.

Dementia becomes more common with age.[15] About 3% of people between the ages of 6574 have dementia, 19% between 75 and 84 and nearly half of those over 85 years of age.[16] The spectrum includes mild cognitive impairment and the neurodegenerative diseases of Alzheimer's disease, cerebrovascular disease, Parkinson's disease and Lou Gehrig's disease. Furthermore, many types of memory decline with ageing, but not semantic memory or general knowledge such as vocabulary definitions, which typically increases or remains steady until late adulthood[17] (see Ageing brain). Intelligence may decline with age, though the rate may vary depending on the type and may in fact remain steady throughout most of the lifespan, dropping suddenly only as people near the end of their lives. Individual variations in rate of cognitive decline may therefore be explained in terms of people having different lengths of life.[18] There are changes to the brain: after 20 years of age there is a 10% reduction each decade in the total length of the brain's myelinated axons.[19]

Age can result in visual impairment, whereby non-verbal communication is reduced,[20] which can lead to isolation and possible depression. Macular degeneration causes vision loss and increases with age, affecting nearly 12% of those above the age of 80.[21] This degeneration is caused by systemic changes in the circulation of waste products and by growth of abnormal vessels around the retina.[22]

A distinction can be made between "proximal ageing" (age-based effects that come about because of factors in the recent past) and "distal ageing" (age-based differences that can be traced back to a cause early in person's life, such as childhood poliomyelitis).[18]

Ageing is among the greatest known risk factors for most human diseases.[2] Of the roughly 150,000 people who die each day across the globe, about two thirds100,000 per daydie from age-related causes. In industrialised nations, the proportion is higher, reaching 90%.[23][24][25]

At present, the biological basis of ageing is unknown, even in relatively simple and short-lived organisms. Less still is known about mammalian ageing, in part due to the much longer lives in even small mammals such as the mouse (around 3 years). A primary model organism for studying ageing is the nematode C. elegans, thanks to its short lifespan of 23 weeks, the ability to easily perform genetic manipulations or suppress gene activity with RNA interference, and other factors.[26] Most known mutations and RNA interference targets that extend lifespan were first discovered in C. elegans.[27]

Factors that are proposed to influence biological ageing[28] fall into two main categories, programmed and damage-related. Programmed factors follow a biological timetable, perhaps a continuation of the one that regulates childhood growth and development. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defence responses. Damage-related factors include internal and environmental assaults to living organisms that induce cumulative damage at various levels.[29]

There are three main metabolic pathways which can influence the rate of ageing:

It is likely that most of these pathways affect ageing separately, because targeting them simultaneously leads to additive increases in lifespan.[31]

The rate of ageing varies substantially across different species, and this, to a large extent, is genetically based. For example, numerous perennial plants ranging from strawberries and potatoes to willow trees typically produce clones of themselves by vegetative reproduction and are thus potentially immortal, while annual plants such as wheat and watermelons die each year and reproduce by sexual reproduction. In 2008 it was discovered that inactivation of only two genes in the annual plant Arabidopsis thaliana leads to its conversion into a potentially immortal perennial plant.[32]

Clonal immortality apart, there are certain species whose individual lifespans stand out among Earth's life-forms, including the bristlecone pine at 5062 years[33] (however Hayflick states that the bristlecone pine has no cells older than 30 years), invertebrates like the hard clam (known as quahog in New England) at 508 years,[34] the Greenland shark at 400 years,[35] fish like the sturgeon and the rockfish, and the sea anemone[36] and lobster.[37][38] Such organisms are sometimes said to exhibit negligible senescence.[39] The genetic aspect has also been demonstrated in studies of human centenarians.

In laboratory settings, researchers have demonstrated that selected alterations in specific genes can extend lifespan quite substantially in yeast and roundworms, less so in fruit flies and less again in mice. Some of the targeted genes have homologues across species and in some cases have been associated with human longevity.[40]

Caloric restriction and exercise are two ways to activate autophagy and inhibit mTOR which can help resolve common age-related health problems.[citation needed]

Caloric restriction substantially affects lifespan in many animals, including the ability to delay or prevent many age-related diseases.[80] Typically, this involves caloric intake of 6070% of what an ad libitum animal would consume, while still maintaining proper nutrient intake.[80] In rodents, this has been shown to increase lifespan by up to 50%;[81] similar effects occur for yeast and Drosophila.[80] No lifespan data exist for humans on a calorie-restricted diet,[54] but several reports support protection from age-related diseases.[82][83] Two major ongoing studies on rhesus monkeys initially revealed disparate results; while one study, by the University of Wisconsin, showed that caloric restriction does extend lifespan,[84] the second study, by the National Institute on Ageing (NIA), found no effects of caloric restriction on longevity.[85] Both studies nevertheless showed improvement in a number of health parameters. Notwithstanding the similarly low calorie intake, the diet composition differed between the two studies (notably a high sucrose content in the Wisconsin study), and the monkeys have different origins (India, China), initially suggesting that genetics and dietary composition, not merely a decrease in calories, are factors in longevity.[54] However, in a comparative analysis in 2014, the Wisconsin researchers found that the allegedly non-starved NIA control monkeys in fact are moderately underweight when compared with other monkey populations, and argued this was due to the NIA's apportioned feeding protocol in contrast to Wisconsin's truly unrestricted ad libitum feeding protocol. [86] They conclude that moderate calorie restriction rather than extreme calorie restriction is sufficient to produce the observed health and longevity benefits in the studied rhesus monkeys.[87]

In his book How and Why We Age, Hayflick says that caloric restriction may not be effective in humans, citing data from the Baltimore Longitudinal Study of Aging which shows that being thin does not favour longevity.[need quotation to verify][88] Similarly, it is sometimes claimed that moderate obesity in later life may improve survival, but newer research has identified confounding factors such as weight loss due to terminal disease. Once these factors are accounted for, the optimal body weight above age 65 corresponds to a leaner body mass index of 23 to 27.[89]

Alternatively, the benefits of dietary restriction can also be found by changing the macro nutrient profile to reduce protein intake without any changes to calorie level, resulting in similar increases in longevity.[90][91] Dietary protein restriction not only inhibits mTOR activity but also IGF-1, two mechanisms implicated in ageing.[52] Specifically, reducing leucine intake is sufficient to inhibit mTOR activity, achievable through reducing animal food consumption.[92][93]

The Mediterranean diet is credited with lowering the risk of heart disease and early death.[94][95] The major contributors to mortality risk reduction appear to be a higher consumption of vegetables, fish, fruits, nuts and monounsaturated fatty acids, i.e., olive oil.[96]

The amount of sleep has an impact on mortality. People who live the longest report sleeping for six to seven hours each night.[97][98] Lack of sleep (<5 hours) more than doubles the risk of death from cardiovascular disease, but too much sleep (>9 hours) is associated with a doubling of the risk of death, though not primarily from cardiovascular disease.[99] Sleeping more than 7 to 8 hours per day has been consistently associated with increased mortality, though the cause is probably other factors such as depression and socioeconomic status, which would correlate statistically.[100] Sleep monitoring of hunter-gatherer tribes from Africa and from South America has shown similar sleep patterns across continents: their average sleeping duration is 6.4 hours (with a summer/winter difference of 1 hour), afternoon naps (siestas) are uncommon, and insomnia is very rare (tenfold less than in industrial societies).[101]

Physical exercise may increase life expectancy.[102] People who participate in moderate to high levels of physical exercise have a lower mortality rate compared to individuals who are not physically active.[103] Moderate levels of exercise have been correlated with preventing aging and improving quality of life by reducing inflammatory potential.[104] The majority of the benefits from exercise are achieved with around 3500 metabolic equivalent (MET) minutes per week.[105] For example, climbing stairs 10 minutes, vacuuming 15 minutes, gardening 20 minutes, running 20 minutes, and walking or bicycling for 25 minutes on a daily basis would together achieve about 3000 MET minutes a week.[105]

Avoidance of chronic stress (as opposed to acute stress) is associated with a slower loss of telomeres in most but not all studies,[106][107] and with decreased cortisol levels. A chronically high cortisol level compromises the immune system, causes cardiac damage/arterosclerosis and is associated with facial ageing, and the latter in turn is a marker for increased morbidity and mortality.[108][109] Stress can be countered by social connection, spirituality, and (for men more clearly than for women) married life, all of which are associated with longevity.[110][111][112]

The following drugs and interventions have been shown to retard or reverse the biological effects of ageing in animal models, but none has yet been proven to do so in humans.

Evidence in both animals and humans suggests that resveratrol may be a caloric restriction mimetic.[113]

As of 2015 metformin was under study for its potential effect on slowing ageing in the worm C.elegans and the cricket.[114] Its effect on otherwise healthy humans is unknown.[114]

Rapamycin was first shown to extend lifespan in eukaryotes in 2006 by Powers et al. who showed a dose-responsive effect of rapamycin on lifespan extension in yeast cells.[115] In a 2009 study, the lifespans of mice fed rapamycin were increased between 28 and 38% from the beginning of treatment, or 9 to 14% in total increased maximum lifespan. Of particular note, the treatment began in mice aged 20 months, the equivalent of 60 human years.[116] Rapamycin has subsequently been shown to extend mouse lifespan in several separate experiments,[117][118] and is now being tested for this purpose in nonhuman primates (the marmoset monkey).[119]

Cancer geneticist Ronald A. DePinho and his colleagues published research in mice where telomerase activity was first genetically removed. Then, after the mice had prematurely aged, they restored telomerase activity by reactivating the telomerase gene. As a result, the mice were rejuvenated: Shrivelled testes grew back to normal and the animals regained their fertility. Other organs, such as the spleen, liver, intestines and brain, recuperated from their degenerated state. "[The finding] offers the possibility that normal human ageing could be slowed by reawakening the enzyme in cells where it has stopped working" says Ronald DePinho. However, activating telomerase in humans could potentially encourage the growth of tumours.[120]

Most known genetic interventions in C. elegans increase lifespan by 1.5 to 2.5-fold. As of 2009[update], the record for lifespan extension in C. elegans is a single-gene mutation which increases adult survival by tenfold.[27] The strong conservation of some of the mechanisms of ageing discovered in model organisms imply that they may be useful in the enhancement of human survival. However, the benefits may not be proportional; longevity gains are typically greater in C. elegans than fruit flies, and greater in fruit flies than in mammals. One explanation for this is that mammals, being much longer-lived, already have many traits which promote lifespan.[27]

Some research effort is directed to slow ageing and extend healthy lifespan.[121][122][123]

The US National Institute on Aging currently funds an intervention testing programme, whereby investigators nominate compounds (based on specific molecular ageing theories) to have evaluated with respect to their effects on lifespan and age-related biomarkers in outbred mice.[124] Previous age-related testing in mammals has proved largely irreproducible, because of small numbers of animals and lax mouse husbandry conditions.[citation needed] The intervention testing programme aims to address this by conducting parallel experiments at three internationally recognised mouse ageing-centres, the Barshop Institute at UTHSCSA, the University of Michigan at Ann Arbor and the Jackson Laboratory.

Several companies and organisations, such as Google Calico, Human Longevity, Craig Venter, Gero,[125]SENS Research Foundation, and Science for Life Extension in Russia,[126] declared stopping or delaying ageing as their goal.

Prizes for extending lifespan and slowing ageing in mammals exist. The Methuselah Foundation offers the Mprize. Recently, the $1 Million Palo Alto Longevity Prize was launched. It is a research incentive prize to encourage teams from all over the world to compete in an all-out effort to "hack the code" that regulates our health and lifespan. It was founded by Joon Yun.[127][128][129][130][131]

Different cultures express age in different ways. The age of an adult human is commonly measured in whole years since the day of birth. Arbitrary divisions set to mark periods of life may include: juvenile (via infancy, childhood, preadolescence, adolescence), early adulthood, middle adulthood, and late adulthood. More casual terms may include "teenagers," "tweens," "twentysomething", "thirtysomething", etc. as well as "vicenarian", "tricenarian", "quadragenarian", etc.

Most legal systems define a specific age for when an individual is allowed or obliged to do particular activities. These age specifications include voting age, drinking age, age of consent, age of majority, age of criminal responsibility, marriageable age, age of candidacy, and mandatory retirement age. Admission to a movie for instance, may depend on age according to a motion picture rating system. A bus fare might be discounted for the young or old. Each nation, government and non-governmental organisation has different ways of classifying age. In other words, chronological ageing may be distinguished from "social ageing" (cultural age-expectations of how people should act as they grow older) and "biological ageing" (an organism's physical state as it ages).[132]

In a UNFPA report about ageing in the 21st century, it highlighted the need to "Develop a new rights-based culture of ageing and a change of mindset and societal attitudes towards ageing and older persons, from welfare recipients to active, contributing members of society."[133] UNFPA said that this "requires, among others, working towards the development of international human rights instruments and their translation into national laws and regulations and affirmative measures that challenge age discrimination and recognise older people as autonomous subjects."[133] Older persons make contributions to society including caregiving and volunteering. For example, "A study of Bolivian migrants who [had] moved to Spain found that 69% left their children at home, usually with grandparents. In rural China, grandparents care for 38% of children aged under five whose parents have gone to work in cities."[133]

Population ageing is the increase in the number and proportion of older people in society. Population ageing has three possible causes: migration, longer life expectancy (decreased death rate) and decreased birth rate. Ageing has a significant impact on society. Young people tend to have fewer legal privileges (if they are below the age of majority), they are more likely to push for political and social change, to develop and adopt new technologies, and to need education. Older people have different requirements from society and government, and frequently have differing values as well, such as for property and pension rights.[134]

In the 21st century, one of the most significant population trends is ageing.[135] Currently, over 11% of the world's current population are people aged 60 and older and the United Nations Population Fund (UNFPA) estimates that by 2050 that number will rise to approximately 22%.[133] Ageing has occurred due to development which has enabled better nutrition, sanitation, health care, education and economic well-being. Consequently, fertility rates have continued to decline and life expectancy have risen. Life expectancy at birth is over 80 now in 33 countries. Ageing is a "global phenomenon," that is occurring fastest in developing countries, including those with large youth populations, and poses social and economic challenges to the work which can be overcome with "the right set of policies to equip individuals, families and societies to address these challenges and to reap its benefits."[136]

As life expectancy rises and birth rates decline in developed countries, the median age rises accordingly. According to the United Nations, this process is taking place in nearly every country in the world.[137] A rising median age can have significant social and economic implications, as the workforce gets progressively older and the number of old workers and retirees grows relative to the number of young workers. Older people generally incur more health-related costs than do younger people in the workplace and can also cost more in worker's compensation and pension liabilities.[138] In most developed countries an older workforce is somewhat inevitable. In the United States for instance, the Bureau of Labor Statistics estimates that one in four American workers will be 55 or older by 2020.[138]

Among the most urgent concerns of older persons worldwide is income security. This poses challenges for governments with ageing populations to ensure investments in pension systems continues in order to provide economic independence and reduce poverty in old age. These challenges vary for developing and developed countries. UNFPA stated that, "Sustainability of these systems is of particular concern, particularly in developed countries, while social protection and old-age pension coverage remain a challenge for developing countries, where a large proportion of the labour force is found in the informal sector."[133]

The global economic crisis has increased financial pressure to ensure economic security and access to health care in old age. In order to elevate this pressure "social protection floors must be implemented in order to guarantee income security and access to essential health and social services for all older persons and provide a safety net that contributes to the postponement of disability and prevention of impoverishment in old age."[133]

It has been argued that population ageing has undermined economic development.[139] Evidence suggests that pensions, while making a difference to the well-being of older persons, also benefit entire families especially in times of crisis when there may be a shortage or loss of employment within households. A study by the Australian Government in 2003 estimated that "women between the ages of 65 and 74 years contribute A$16 billion per year in unpaid caregiving and voluntary work. Similarly, men in the same age group contributed A$10 billion per year."[133]

Due to increasing share of the elderly in the population, health care expenditures will continue to grow relative to the economy in coming decades. This has been considered as a negative phenomenon and effective strategies like labour productivity enhancement should be considered to deal with negative consequences of ageing.[140]

In the field of sociology and mental health, ageing is seen in five different views: ageing as maturity, ageing as decline, ageing as a life-cycle event, ageing as generation, and ageing as survival.[141] Positive correlates with ageing often include economics, employment, marriage, children, education, and sense of control, as well as many others. The social science of ageing includes disengagement theory, activity theory, selectivity theory, and continuity theory. Retirement, a common transition faced by the elderly, may have both positive and negative consequences.[142] As cyborgs currently are on the rise some theorists argue there is a need to develop new definitions of ageing and for instance a bio-techno-social definition of ageing has been suggested.[143]

With age inevitable biological changes occur that increase the risk of illness and disability. UNFPA states that,[136]

"A life-cycle approach to health care one that starts early, continues through the reproductive years and lasts into old age is essential for the physical and emotional well-being of older persons, and, indeed, all people. Public policies and programmes should additionally address the needs of older impoverished people who cannot afford health care."

Many societies in Western Europe and Japan have ageing populations. While the effects on society are complex, there is a concern about the impact on health care demand. The large number of suggestions in the literature for specific interventions to cope with the expected increase in demand for long-term care in ageing societies can be organised under four headings: improve system performance; redesign service delivery; support informal caregivers; and shift demographic parameters.[144]

However, the annual growth in national health spending is not mainly due to increasing demand from ageing populations, but rather has been driven by rising incomes, costly new medical technology, a shortage of health care workers and informational asymmetries between providers and patients.[145] A number of health problems become more prevalent as people get older. These include mental health problems as well as physical health problems, especially dementia.

It has been estimated that population ageing only explains 0.2 percentage points of the annual growth rate in medical spending of 4.3% since 1970. In addition, certain reforms to the Medicare system in the United States decreased elderly spending on home health care by 12.5% per year between 1996 and 2000.[146]

Positive self-perception of health has been correlated with higher well-being and reduced mortality in the elderly.[147][148] Various reasons have been proposed for this association; people who are objectively healthy may naturally rate their health better than that of their ill counterparts, though this link has been observed even in studies which have controlled for socioeconomic status, psychological functioning and health status.[149] This finding is generally stronger for men than women,[148] though this relationship is not universal across all studies and may only be true in some circumstances.[149]

As people age, subjective health remains relatively stable, even though objective health worsens.[150] In fact, perceived health improves with age when objective health is controlled in the equation.[151] This phenomenon is known as the "paradox of ageing." This may be a result of social comparison;[152] for instance, the older people get, the more they may consider themselves in better health than their same-aged peers.[153] Elderly people often associate their functional and physical decline with the normal ageing process.[154][155]

The concept of successful ageing can be traced back to the 1950s and was popularised in the 1980s. Traditional definitions of successful ageing have emphasised absence of physical and cognitive disabilities.[156] In their 1987 article, Rowe and Kahn characterised successful ageing as involving three components: a) freedom from disease and disability, b) high cognitive and physical functioning, and c) social and productive engagement.[157]

The ancient Greek dramatist Euripides (5th century BC) describes the multiply-headed mythological monster Hydra as having a regenerative capacity which makes it immortal, which is the historical background to the name of the biological genus Hydra. The Book of Job (c. 6th century BC) describes human lifespan as inherently limited and makes a comparison with the innate immortality that a felled tree may have when undergoing vegetative regeneration.[158]

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Nir Barzilai, M.D. Director of the Institute for Aging

Research Director of the Nathan Shock Center of Excellence in the Basic Biology of Aging

Ingeborg and Ira Leon Rennert Chair of Aging Research

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The Longevity Genes Project

What if people could live to be 100 and beyond and still be healthy, active and engaged?

What if there were a way to age without a slow and painful decline?

In the Longevity Genes Project at Albert Einstein College of Medicine, Dr. Nir Barzilai and his team conducted genetic research on more than 500 healthy elderly people between the ages of 95 and 112 and on their children.

The identification of longevity genes by Einstein researchers could lead to new drug therapies that might help people live longer, healthier lives and avoid or significantly delay age-related diseases such as Alzheimer's disease, type 2 diabetes and cardiovascular disease.

The Longevity Genes Project Video Series

This video series includes informative interviews with Dr. Nir Barzilai, who leads the Einstein longevity research efforts, and with four study participants whose diverse and compelling stories will inspire you. We invite you to view all of the videos and leave comments. Click on the links below to view each segment.

Research: Dr. Nir Barzilai

Personal Profiles: Lilly Port: Age 96 | Harold Laufman: Age 98 | Irma Daniel: Age 103 | Irving Kahn: Age 104

Longevity and Longenity Information and preliminary results of Einstein's search for longevity genes in the Jewish Ashkenazi population and genotypes and phenotypes for exceptional longevity.

Why Ashkenazi Jews? Information about the "founder effect" and the historically unique Ashkenazi Jewish population.

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Longevity Genes Project | Institute for Aging Research ...

Whats the secret to living longer? Scientists have been pondering this for some time now and while we understand that various lifestyle and environmental factors contribute to our longevity, it is also evident that genetics plays a role. In fact, family studies have indicated that genetic factors account for around 20-30% of the variation in adult lifespan. So what are these genetic secrets to longevity? A new study, published in Aging Cell, may have some answers.

Previous work identified a couple of candidate genes that researchers suspect may play a role in longevity. The genes identified were apolipoprotein E (APOE), which transports cholesterol around the body, and FOXO3A which may affect insulin sensitivity. Variations in these genes were found to be associated with longevity; however, neither had a large influence, which left scientists suspecting that there must be other factors at play.

To find out more, researchers from the Spanish National Cancer Research Center scoured the protein-coding genes, or exomes, of members of three separate families that all had exceptionally long-lived members. Three of the individuals sequenced lived to be 103 or older, and their siblings lived to be 97 or older. They then compared these with sequence data from 800 other people that acted as controls.

They found that rare variants in one particular gene cropped up in all three familiesapolipoprotein B (APOB). Like the APOE protein, APOB is a cholesterol transporter. APOB helps to carry bad cholesterol, or low-density lipoprotein (LDL), in the blood. While our bodies need cholesterol, LDL has a bad rep because it can build up along the walls of blood vessels, blocking arteries and eventually leading to heart attacks in some.

Its possible that these genetic variations reduce the levels of LDL in the blood, an idea that the researchers are now investigating. According to lead author Timothy Cash, if the long-lived individuals do have lower cholesterol levels, it would reinforce the idea that cardiovascular health is an important factor in the aging process. Interestingly, variations in APOE are also known risk factors for cardiovascular disease, which is likely due to elevated lipid levels.

[ViaNew ScientistandAging Cell]

Excerpt from:
Genetic Secrets Of Longevity Discovered | IFLScience

Longevity, i.e., the property of being long-lived, has its natural limitation in the aging process. Longevity has a strong genetic component, as has become apparent from studies with a variety of organisms, from yeast to humans. Genetic screening efforts with invertebrates have unraveled multiple genetic pathways that suggest longevity is promoted through the manipulation of metabolism and the resistance to oxidative stress. To some extent, these same mechanisms appear to act in mammals also, despite considerable divergence during evolution. Thus far, evidence from population-based studies with humans suggests the importance of genes involved in cardiovascular disease as important determinants of longevity. The challenge is to test if the candidate longevity genes that have emerged from studies with model organisms exhibit genetic variation for life span in human populations. Future investigations are likely to involve large-scale case-control studies, in which large numbers of genes, corresponding to entire gene functional modules, will be assessed for all possible sequence variation and associated with detailed phenotypic information on each individual over extended periods of time. This should eventually unravel the genetic factors that contribute to each particular aging phenotype.

See more here:
Genetics of longevity and aging.

Evidence-Based Gerontology

One of the most important things about the Okinawa Centenarian Study is the fact that it is based on solid evidence. The most important evidence needed for any centenarian study is reliable age-verification data. Throughout Japan (including Okinawa prefecture), every city, town, and village records birth, marriage and death data (among other data) in a koseki (family register). This system was instituted throughout Japan in the 1870's. The koseki is supplemented by a regular census undertaken every five years. Life tables calculated from this database show one of the world's longest life expectancies and prevalence data show the world's highest known concentration of centenarians for any country or state.

After examining over 900 Okinawan centenarians and numerous other elderly in their seventies, eighties, and nineties, some fascinating findings have emerged. One, genetic factors appear important to human longevity, including Okinawan longevity. Two, it has also become clear that the Okinawan lifestyle provides many reasons why older Okinawans are so remarkably healthy so far into their senior years. Discovering the reasons for the apparent genetic and environmental advantages could have an important impact on our health and well-being in the West. Below appear some of the key findings and what they mean in terms of healthy aging -- for the Okinawans, and the rest of us.

Identifying factors that help us remain healthy, vigorous and disability-free at older ages is one of our major research priorities. Since the completion of the Human Genome Project and the HapMap Project (a project to identify common variations in human genes), a promising novel strategy by some human longevity researchers is to try to identify genes (and variations of those genes) that impact human aging and longevity. If such genes and their genetic pathways can be identified then novel therapies might be created that affect the biology of these pathways. This may help prevent or treat age-associated diseases and perhaps even slow aging itself. Such therapies might include interventions as simple as diet and focused exercise, specific food compounds, neutraceuticals or pharmaceuticals.

How much of human longevity is due to genes? Estimates of the heritability of human lifespan vary from 10-50% with the most common finding being that about a third of human lifespan may be heritable. Phenotypes that suggest slower aging, such as survival to 90+ years, may have an even stronger genetic basis, which explains why centenarians and near-centenarians tend to cluster in families. But until the discovery of the apolipoprotein E (ApoE) gene, there was little evidence for a single gene effect large enough to impact human longevity. This discovery has been replicated in many populations, suggests that associations with some genes are large.

Studies of long-lived humans, such as American centenarians, have helped identify other promising genetic loci for longevity and healthy aging. However, these studies are often limited in scope due to small sample sizes, genetic admixture, and inappropriate selection of controls. Some success has been achieved through use of genetically homogeneous populations with smaller gene pools.

Our research group was the first to identify so called "human longevity genes" using centenarians as a study model when we published a study showing that Okinawan centenarians have HLA (human leukocyte antigen) genetic polymorphisms that place them at lower risk for inflammatory and autoimmune diseases (see figure below: Takata et al., Lancet 1987).

We also studied the mortality patterns of centenarian siblings. Past family studies in other populations have shown that there are familial (genetic) components to longevity. That is, longevity tends to run in families. In support of this, we found that a mortality advantage exists for centenarian siblings versus their age-matched birth cohorts. This advantage appears sustained over the course of the siblings' lives. At each 5-year age interval until age 90 years, siblings of Okinawan centenarians maintained approximately a 50% lower mortality risk. This resulted in an average of 11.8 years extra lifespan compared to their age-matched birth cohort. The sustained mortality advantage over the life course provides further evidence that human longevity has an important genetic component since most environmental mortality advantages, such as education, diminish or disappear completely in older age groups (see figure below from Willcox BJ et al. Siblings of Okinawan centenarians exhibit lifelong mortality advantages. J Gerontol A Biol Sci Med Sci. 2006;61:345-54).

In order to quantify the genetic contribution to Okinawan longevity, we studied the sibling recurrence risk ratio or "lambda of sib (ls)" in siblings of Okinawan centenarians. This is a calculation that has been shown to give a rough idea of how important genes might be to a given phenotype, such as a disease, or even to something more complex like human longevity.

We analyzed a population-based sample of 348 Okinawan centenarians (born between 1874 and 1902) and 969 of their siblings (507 females and 462 males) to explore the feasibility of a genome-wide study of Okinawan longevity. The ls for Okinawan centenarians was 6.5 (95% confidence interval: 3.9-10.7) for females and 5.1 (95% confidence interval: 1.8-14.2) for males, respectively. The weighted sex-combined ls was 6.3. These estimates in Okinawans appear to be higher than those obtained in past work on U.S. Caucasians. For example, a study of the familial component of longevity in Utah families estimated the ls to be 2.3. This suggests an important genetic component to Okinawan longevity and supports further work on the genetics of healthy aging and longevity in this population (see Willcox BJ et al., Substantial advantage for longevity in siblings of Okinawan centenarians. Genetic Epidemiology). 2005;29:286.

Does this mean that Okinawan longevity is all genetic? Not at all. We believe the Okinawans have both genetic and non-genetic longevity advantages -- the best combination. In fact, we have written extensively that the Okinawan traditional way of life -- the dietary habits, the physical activity, the psychological and social aspects, all play an important role in Okinawan longevity.

While most studies of humans have suggested that about a third of human longevity is due to genetics, this depends on the age, sex, ethnicity and environment of the study population. For example, studies of "model organisms" of aging, such as rodents, who share many of the same genes as humans, have shown that single genes can influence lifespan by 50% or more. On the other hand, studies of lifestyle interventions, such as eating fewer calories (a.k.a. "caloric restriction") have shown that this dietary intervention can also yield increases in lifespan of a similar magnitude (see Willcox DC et al., Caloric restriction and human longevity: what can we learn from the Okinawans? Biogerontology. 2006;7:173-77). The key is to study both genetic and non-genetic (environmental) factors and ultimately "gene-environment" interactions that lead to healthy longevity.

One of the most durable theories of aging is the free radical theory. This theory postulates that damage from free radicals (unstable molecules), generated mainly from metabolizing food into energy, ultimately damages vital body molecules (tissue, DNA, etc.). This damage accumulates with time until, like an old car, we fall apart. In support of this theory, one of the most important findings in free-radical research has been that eating fewer calories increases life span (Sohal RS, et al. Science 1996;273:59-63; Heilbronn LK, et al. Am J Clin Nutr 2003;78:361-9). The initial evidence that this may work in humans has been indirect and based on observation of the low caloric intake of the Okinawans and their long life expectancy (Willcox DC, et al. Biogerontology 2006). More direct evidence suggests that Okinawans following the traditional ways have low blood levels of free radicals. The elders had significantly lower levels of lipid peroxide-compelling evidence that they suffer less free-radical-induced damage. This may indicate healthier lifestyles but may also be due to gene variants that result in lower blood levels of free radicals. This is currently under investigation.

Levels of Lipid Peroxides in Okinawan Centenarians and Septuagenarians

Elderly Okinawans were found to have impressively young, clean arteries, low cholesterol, and low homocysteine levels when compared to Westerners. These factors help reduce their risk for coronary heart disease by up to 80% and keep stroke levels low.

Their healthy arteries appear to be in large part due to their lifestyle: diet, regular exercise, moderate alcohol use, avoidance of smoking, blood pressure control, and a stress-minimizing psychospiritual outlook. However, there are also potential genetic aspects such as lower fibrinogen levels possibly due to differences in fibrinogen-related genes. A recent autopsy study that we conducted on a centenarian demonstrated that her coronary arteries were virtually free of atherosclerotic plague (Bernstein, Willcox et al. JGMS 2004).

The chart to the right indicates that the higher the plasma homocysteine (a new risk factor) level is, the more people suffer from cardiovascular disease. Homocysteine is an amino acid that causes damage to arterial walls. It is higher in people who don't get enough folate (e.g. green leafy vegetables) and vitamins B6, B12 but low in Okinawans.

Okinawans are at extremely low risk for hormone-dependent cancers including cancers of the breast, prostate, ovaries, and colon. Compared to North Americans, they have 80% less breast cancer and prostate cancer, and less than half the ovarian and colon cancers. Some of the most important factors that may protect against those cancers include low caloric intake, high vegetables/fruits consumption, higher intake of good fats (omega-3, mono-unsaturated fat), high fiber diet, high flavonoid intake, low body fat level, and high level of physical activity.

Hormone-Dependent Cancer Risk

Yearly Cancer Deaths (per 100,000 people)

Adapted from World Health Organization 1996; Japan Ministry of Health and Welfare 1996

NK, a typical healthy centenarian was reported to be in particularly good health, completely independent, and still farming. He is shown here getting his bone density tested by heel bone ultrasound.

Okinawans have about 20% fewer hip fractures than do mainland Japanese, and Japanese have about 40% fewer hip fractures than Americans (Ross PD, et al. Am J Epidemiol 1991;133:801-9). Our research on Okinawan elders showed that their bone density, when adjusted for body size, is similar to Americans, and like the rest of us they continue to lose bone mass as they get older, but possibly at a slower rate. We compared bone mineral density in a group of Okinawans to two groups from mainland Japan and found that by age forty for women and age fifty for men the groups began to diverge. The Japanese began to lose significantly more calcium from their bones than the Okinawans, suggesting the Okinawans preserve their bone density at healthy levels for longer periods of time than other Japanese (Suzuki M, et al. Japanese J Bone Res 1995;63:166-72). Protective lifestyle factors that may play a role here include high calcium intake by Okinawans in both food and their natural drinking water, high vitamin D levels from exposure to sunlight, increased physical activity, especially at older ages, and high intake of dietary flavonoids (estrogenic compounds from plant foods).

Prevalence surveys suggest that the dementia rate is fairly low among the Okinawan elderly, compared to other elderly populations. Even into their late 90s Okinawans suffered lower dementia rates than reported for comparable populations in the United States and elsewhere.

Photo: 97 year old karate master Seikichi Uehara

Okinawan centenarians have been lean throughout their extraordinarily long lives, with an average body mass index (BMI) that ranged from 18 to 22 (lean is less than 23). The Okinawans have traditionally kept eating a low-calorie, low glycemic load diet, practicing calorie control in a cultural habit known as hara hachi bu (only eating until they are 80% full), and keeping physically active the natural way. Particular exercise interventions are under study for their role in healthy aging.

Women's health and aging is one of our research interests. For example, women in Okinawa tend to experience menopause naturally and nonpharmacologically with fewer complications such as hot flashes, hip fractures, or coronary heart disease. Lifestyle determinants include diet, avoidance of smoking and exercise in the form of dance, soft martial arts, walking and gardening. Okinawan women also have a very high intake of natural estrogens through their diet, mainly from the large quantities of soy they consume. Soy contains phytoestrogens, or plant estrogens called flavonoids. The other important major phytoestrogens are lignans, which are derived from flax and other grains. All plants, especially legumes (beans, peas), onions, and broccoli, contain these natural estrogens, but not nearly in the same quantity as soy and flax. Recent double-blind placebo controlled studies support the ability of soy isoflavones to slow the bone loss (Alekel D, et al. Am J Clin Nutr 2001;72:844-52) and hot flashes (Albertazzi P, et al. Obstet Gynecol 1998;91:6-11) that occur with menopause.

Okinawan elders may have higher levels of sex hormones, including natural DHEA, estrogen, and testosterone than similarly aged Americans, suggesting that the Okinawans are physiologically younger. DHEA is a steroid produced in the human adrenal gland, and some studies suggest that it may help ameliorate the ravages of aging. However, taking DHEA supplements could increase risk for breast and other cancers so we do not recommend taking DHEA supplements. More supported by the scientific literature is that DHEA levels decline in direct ratio with age, so it may be a good marker of biological age. Okinawans appear to have higher DHEA levels than similarly aged Americans suggesting that Okinawans may age slower than Americans. As Okinawans age, both sexes maintain remarkably higher levels of estrogen which may help protect against heart disease and osteoporosis. Testosterone is the male equivalent of estrogen. Higher endogenous levels increase our muscle mass and our body hair, deepen our voices, and control our libidos, among other functions. This hormone also appears higher in older Okinawan men. Cross-national population studies are needed to confirm these differences and their biological significance.

See more here:
The Okinawa Centenarian Study : Evidence based gerontology

Scientists may be able to make substantial gains in extending not only the length of human life, but the quality of life as we age, according to many researchers. That won't be limited to breakthroughs in the laboratory. To a significant extent, it will depend on how we live our lives.

As for the scientists, first they have to answer a very basic question. Why do humans live longer than any other mammals?

For starters, we are big. Long ago scientists recognized a relationship between body size and longevity. Humans just narrowly edge out the elephant (so size isn't the whole story) to win the Olympic gold for living longer, but recent research reveals that's just part of the story.

We also have huge brains compared to the size of our bodies. We are mobile, have few predators except for other humans, and there's a drugstore on every corner.

It wasn't always that way. During most of recorded history any human who reached the mid thirties had beaten the system. Over the past century we gained a global average of 30 years, about 25 of which are attributed to improvements in public health, according to federal statistics.

Today, the global life expectancy is 67.2 years. It's around 78 years in the United States, and a few years more in Japan, the world leader for sticking around.

Genetics, of course, play a key role in longevity. In recent years, when we entered the golden age of genetics, many hoped to discover the "longevity gene" that allowed an increasing number of humans to live more than a century. For awhile, they thought they had found it.

One gene produces sirtuins, a protein thought to increase lifespan in several organisms, and that protein quickly became the darling of producers of anti-aging creams. But last year an international team of researchers found that sirtuins have no effect on animal longevity.

That came as no surprise to scientists at the University of California, San Francisco, who had determined that there is no longevity gene. As has often been the case in genetics in recent years, it's much more complicated than that.

It turns out that there are many genes that affect lifespan, but each of those genes has a very limited role. The San Francisco researchers found that some genes make proteins that fight bacterial infections, while others ward off oxidative stress and protein damage, commonly associated with aging. But all these genes don't just do their own thing. They are apparently controlled by at least two other genes that act as drill sergeants. Research by these scientists found that when all these genes work right, the lifespan of the roundworm, C. elegans, doubled. That worm is used in much research because it is a simple organism that shares many genes with humans.

But will the same thing work for humans? Maybe.

In a related study, scientists at the University of Liverpool reported earlier this year that some proteins change over time in long living species, including humans. Joao Pedro Magalhaes and his colleagues studied 30 mammals and found that these proteins evolve during the course of the lifetime "to cope with biological processes impacted by aging, such as DNA damage." In other words, animals that live longer are better equipped to make repairs in tissues and organs that help them fight the aging process.

There is a huge body of evidence showing that size really does matter, both in terms of body mass and cerebral tissue. Researchers in Barcelona studied 493 mammal species and found that a larger brain leads to a longer life.

A smarter animal is better equipped to deal with environmental challenges and less likely to take silly chances, like picking a fight with a much bigger animal. That may seem obvious, but it's less clear why body size should contribute to longer lifespan. Among mammals, the top four are humans, followed by elephants, horses and hippopotamuses, but most likely the hippo wouldn't score all that high on an IQ test.

The turkey buzzard tops the list for birds at 118 years, maybe because it's smart enough to wait for road kill instead of attacking a live animal.

But the giant tortoise is the real champ. The world mourned the passing of Lonesome George in the Galapagos Islands earlier this year. The actual age of old George is unknown, although it's clear he made it well past the century mark. Among the superachievers was Tu'I Malila, who was presented to the royal family of Tonga by Capt. James Cook in 1777. He was thought to be 188 when he died in 1965. That still leaves the question of why size matters. Adrian Bejan, a mechanical engineering professor at Duke University, has spent years studying the relationship between size and lifespan, and he is out with a new idea.

Bejan argues in a paper published this week in Nature Scientific Reports that big animals live longer because they travel farther, thus giving them access to more resources. Mobility is the key. Get off the couch.

If he's right, then that leaves longevity largely in our own hands. Do the right thing and you'll live longer. Physicians tell us that all the time. Don't smoke. Get plenty of exercise. Eat right. Researchers at Newcastle University in England think they have figured out why something like eating a low calorie diet can increase lifespan. Aging is strongly influenced by senescence, the end of a cell's ability to replicate itself. They fed mice a low calorie diet and the accumulation of senescent cells plummeted, thus defeating much of the aging process.

It worked even for older mice, suggesting that eating less or at least fewer calories may be our best defense against aging and an early death.

No more ice cream? I'm waiting for a magic pill.

Read more from the original source:
Can Humans Live Forever? Longevity Research Suggests ...

Longevity Secrets, practical steps to take to have a longer life, diet, food and supplements Subscribe to a FREE Natural Healing newsletter at Physician Formulas December 15, 2015 by Ray Sahelian, M.D.

In the USA, the two major risk factors for premature death are smoking and high blood pressure. Even in middle age, adopting a healthy lifestyle can lower the risk for heart disease and premature death. A program of healthy eating, exercise and stress reduction can not only reverse some diseases -- it may actually slow down the aging process at the genetic level. The lifestyle changes affected the telomeres -- little caps on the end of the chromosomes that carry the DNA, a team at the University of California, San Francisco reported in December 2013.

Supplements for Longevity and healthier life There is currently no evidence in humans that taking supplements or hormones (such as human growth hormone) will make us live longer. However, it seems reasonably safe to take small amounts of certain supplements that have shown in preliminary research to be helpful.

Antioxidants People think that a longevity secret is to take as many antioxidants in high doses. But more is not necessarily better. If you plan to take them, use low doses, even it means taking a portion of a capsule. Acetyl l-carnitine and the antioxidant lipoic Acid are interesting nutrients that may be beneficial, more research is needed before making recommendations. Acetylcysteine could be of benefit. Carnosine appears to be able to extend the lifespan of cultured cells, and rejuvenate senescent cells. Resveratrol from red wine has potential. Eat a few grapes a week or drink a couple of ounces of wine a few times a week. Wine has many beneficial polyphenols. The compound that makes red wine a healthful drink may also hold one of the secrets to longevity. Researchers found that resveratrol acted on fruit flies and worms in the same way as a method known to extend longevity of animals including monkeys -- sharply restricting how much they eat.. The finding opens the possibility that people could take a pill to achieve the same benefits as strict dieting to live longer, healthier lives, said David Sinclair of Harvard Medical School in Boston, who led the study. "We found this chemical that can extend longevity of every organism we give it to." Royal Jelly has been studied in rodents. Vitamin D supplementation may improve longevity in those who have a low intake of vitamin D.

Nutritional supplements help mice stay healthy with age When mice were supplemented with more than 2 dozen vitamins, minerals nutrients and herbal extracts, they did not experience a 50 per cent loss in daily movement like other non-supplemented animals. The benefits were associated with an improvement in the activity of mitochondria as well as by reducing levels of free radicals. David Rollo, from McMaster University, says, This study obtained a truly remarkable extension of physical function in old mice, far greater than the respectable extension of longevity that we previous documented. This holds great promise for extending the quality of life of health span of humans. David Rollo says that it is unclear if the effects would be repeated in humans and years or decades of clinical trials would be required before any definitive conclusions could be made. The dietary product given to the mice included vitamins B1, B3 (niacin), B6, B12, C, D, E, folic acid, beta-carotene, CoQ10, rutin, bioflavonoids, ginko biloba, ginseng, green tea extract, ginger root extract, garlic, L-Glutathione, magnesium, selenium, potassium, manganese, chromium picolinate, acetyl L-carnitine, melatonin, alpha-lipoic acid, N-acetyl cysteine, acetylsalicylic acid, cod liver oil, and flax seed oil. Dietary amelioration of locomotor, neurotransmitter and mitochondrial aging. Experimental Biology and Medicine 2010.

Longevity enhancers - Secrets and simple steps to take: The field of longevity and anti-aging is full of promises and unsubstantiated claims. As of now, there is no definitive research in humans of any substances or techniques that have been proven to extend longevity. However, there are a number of steps we can take to potentially live longer. These include:

1. Positive Attitude Have a positive attitude and improve your coping skills to daily stress. Embrace the philosophy that "It's not what happens to me, it's what I make of it." In a sample of people aged 50 and older who were followed for an average of 23 years, respondents who reported having a positive attitude toward aging lived an average of more than 7 years longer than those who had a more dismal view of getting older. Do you want to be happier? Take a look at my book on Happiness. A 50-year long study suggests that longevity is improved in men and women who are active, emotionally calm, and organized. Psychosomatic Medicine, July / August 2008. Optimists live longer, healthier lives than pessimists. Researchers at University of Pittsburgh, led Dr. Hilary Tindle, looked at rates of death and chronic health conditions among participants of the Women's Health Initiative study, which has followed more than 100,000 women ages 50 and over since 1994. Women who were optimistic were 14 percent less likely to die from any cause than pessimists and 30 percent less likely to die from heart disease after eight years of follow up in the study. Optimists also were also less likely to have high blood pressure, diabetes or smoke cigarettes. March 2009. Emotionally stable, intelligent men may live longer than neurotic, less intelligent men. Men with neurotic traits -- a tendency to worry and to experience emotional ups and downs -- and lower cognitive ability have a higher mortality rate than men without these traits. Psychosomatic Medicine, 2009. If you feel like you have most things in your life under control, this could make you feel even more confident and you'll probably live longer than other people. Feb. 3, 2014, Health Psychology, online.

People with a bright outlook on the future may live longer than those who take a dimmer view. Researchers in the Netherlands found that older men and women judged to have optimistic personalities were less likely to die over the nine-year study period than those with pessimistic dispositions. Much of this reduced risk was due to lower rates of death from cardiovascular disease among the most optimistic men and women in the study. They were 77 percent less likely to die of a heart attack, stroke or other cardiovascular cause than the most pessimistic group-regardless of factors such as age, weight, smoking and whether they had cardiovascular or other chronic diseases at the study's start. 2. Keep a normal weight Keep a healthy weight and reduce the number of calories consumed, but not to the point of starving. Caloric restriction prolongs life in animals, but less is known in humans. Cutting calories may do more than help people shed excess weight. According to a new report, a low-calorie diet may also slow age-related changes in the heart's genes that can lead to chronic disease. In the study, "middle-aged" 14-month-old mice were fed either a normal diet or one restricted in calories. When the mice reached 30 months of age, or the equivalent of 90 years of a human life span, the researchers analyzed their heart tissue. The hearts of mice on the low-calorie diets showed nearly 20% fewer age-related genetic changes and also appeared to have less DNA damage than those of mice on regular diets. Restricting calories also inhibited potentially disease-causing changes in the immune system, and suppressed apoptosis, or programmed cell death. A telephone poll conducted by ABC News found that 73% of respondents would not restrict their caloric intake in order to live longer. Mouse study: eating less at any age prolongs life. Bottom line: reduce caloric intake, but not to the point of having a miserable time. The size of an aging man's belly and the bulk of his biceps provide a more accurate picture of his mortality risk than body mass index (BMI) alone. As people age they typically lose muscle mass and gain belly fat.

3. What you eat determines how long you live Consume a healthy diet. Reduce consumption of foods cooked at high temperature. Drink more tea, particularly green tea. By relying more on steaming, boiling and stewing to cook foods and using acidic marinades on meat cooked with dry heat, people may be able to stay healthier. These strategies will reduce the amount of advanced glycation end products (AGEs), or glycotoxins that people consume with their food. The more AGEs healthy people eat, the greater their levels of inflammation and oxidative stress. Use the sugar substitute stevia which contains stevioside, a safe sweetener with no calories. Make sure to have more long chained fatty acids in your diet such as omega-3 fatty acids found in fish. Fresh fruit and vegetable consumption of greater than 5 servings a day is associated with progressively longer survival and lower mortality rates. 2013 American Society for Nutrition. Fruit and vegetable consumption and all-cause mortality: a dose-response analysis.

Duke Med Health News. 2013. Vegetarian diets aid longevity, reduce risk of all-cause mortality. But results are more significant in men than women. Further research is needed to determine why.

High total red meat consumption was associated with progressively shorter survival, largely because of the consumption of processed red meat. Consumption of nonprocessed red meat alone was not associated with shorter survival. Differences in survival associated with processed and with nonprocessed red meat consumption. Am J Clin Nutr 2014.

Herbs and spices Consume more culinary herbs and spices such as garlic, onion, curcumin, parsley, mint, and others.

4. Exercise and longevityRegular exercise and being physically active will help you live longer. Regular stretching or yoga is helpful in keeping joints and ligaments supple. If you are sedentary, even a small increase in activity can enhance your longevity by a couple of years. People who engage in plenty of light movement have a lower risk of developing a disability and losing their capacity to care for themselves. People who want to increase longevity may do so by running or engaging in regular activity. In one study done at Stanford University in California, middle-aged members of a runner's club were half as likely to die over a 20-year period as people who did not run. Running reduced the risk not only of heart disease, but of cancer and neurological diseases such as Alzheimer's. Any type of exercise will likely do the trick. Fitness, strength and flexibility do not inevitably fade away with age, and are more often a matter of lifestyle choicest. Often, the discomforts of middle-age, like lower back pain or stiff joints, are blamed on aging alone. However, a well-rounded exercise routine that includes aerobic activity, strength training and stretching can help people offset the effects of aging. Avoid extreme physical activities. Marathon runners have increased stiffness of the large arteries, suggesting that some types of regular high-intensity exercise may actually be bad for the heart, potentially leading to hardening of the arteries, high blood pressure, heart attack and even death. A moderate running regimen -- for instance two to three hours per week appears best for longevity. People who get either no exercise or high-mileage runners both tend to have shorter lifespans than moderate runners. The study was conducted by the Cardiovascular Research Institute at the Lehigh Valley Health Network in Allentown, PA and published in April 2014. Everyone knows that walking limbers the aging body, but did you know it keeps the mind supple as well? Walking can actually boost the connectivity within brain circuits, which tends to diminish as the grey hairs multiply. Frontiers in Aging Neuroscience, Published 2010. Excess TV viewing, such as more than 2 hours a day, shortens lifespan. Almost any amount and type of physical activity may slow aging deep in our cells, and middle age is a critical time to get the process rolling.

Even small changes can help confirmed couch potatoes improve their health and enhance longevity. Although the benefits of exercise and a healthy diet are well known, people may think they have to make major changes in their lifestyle to obtain any results. But any increase in physical activity is beneficial.

Basic lifestyle habits lead to a longer lifespan. Exercise, a healthy diet and good sleep slow down the aging process at a cellular level, and protect the body and mind against the harm caused by stress. July 29, 2014, Molecular Psychiatry

5. Avoid smoking cigarettes. Smokers die ten years younger on average than non-smokers As if smokers need another reason to kick the habit, California scientists have discovered that nornicotine, a byproduct of nicotine, the substance that makes cigarettes so addictive, causes a type of chemical reaction in the body similar to that which occurs when sugar is scorched or food goes bad. This reaction is thought to play a role in diabetes, cancer and other diseases. The interaction between sugars and proteins can produce substances called advanced glycation endproducts, or AGEs. The accumulation of AGEs appears to contribute to the aging process and certain diseases. Guided imagery may help quit smoking. 6. Loving connectoinsHave strong connections to others, whether through family and relatives, marriage, children, pets, or connecting with nature, planet earth, and the universe. Have loving and caring friends. Research suggests that having a strong network of friends helps people live longer.

7. Get a deep sleep. Getting a deep sleep is probably the most important longevity secret.

8. Keep your mind young and active by learning. Doing crossword puzzles or watching the show Jeopardy can do wonders in maintaining mental sharpness and word recall. The more educated you are, the less likely you are to become chronically ill or disabled, and your chances for greater longevity will improve. But, the amount of money you make plays a bigger role in whether your illness progresses.

9. Try to surround yourself with nature. Green trees in the neighborhood, sunshine in the home, are linked to longevity.

10. Tooth care Take care of your teeth and mouth to prevent or minimize gum disease and dental caries. Use a soft brush after a meal and then floss. Smoking can cause gum disease.

Addition longevity tips Work as long as you can. It is widely held that early retirement is associated with longer life expectancy and later retirement is associated with early death. Survival rates appear to improve with increasing age at retirement. This seems to be the case for both high- and low-income groups.

Participating in volunteer activities may add years to an older person's life. Volunteering may improve health by expanding retirees' social networks, increasing their access to resources and improving their sense of self-worth.

Drink more tea, and less sodas and sugared drinks. Limit fruit juice intake to no more than 8 ounces a day since fruit juices have a lot of fructose. Many delicious herbal teas are available, including green tea, ginger, rooibos herb, rose hips, mint, fennel herb, licorice, etc.

10. Limit coffee intake to one or two cups - chronic coffee consumption has a detrimental effect on aortic stiffness and wave reflections, which may increase the risk of cardiovascular or heart disease.

Drink an ounce or two of wine a few times a week.

Do DHEA hormone and pregnenolone hormone increase longevity? In high doses, DHEA and pregnenolone may increase the risk for cancer and heart arrhythmia. But it is possible, that in some people, low doses such as 1 or 2 mg may have health benefits.

Have fun, have more sexual intimacy and increase your pleasure with Passion Rx sexual pleasure pills. The herbs in this formula are Ashwagandha herb, Catuaba herb, Cnidium herb, Choline, DMAE brain enhancer, Muira Puama, Tribulus, Tongkat ali, and a version with Yohimbe herb.

Additional longevity enhancers: Being financially stable Having a satisfying career Healing old and new emotional wounds Having a personal religious or philosophical belief system that gives meaning to this world. Driving safely, wearing seat belts, minimizing the use of cell phones while driving.

Genetics One of the most important influences on longevity is genetics, something we cannot influence with our present scientific knowledge. People who have parents and grandparents who live long are more likely to also live a long life.

High blood pressure and longevity Hypertension can take years off both life expectancy and time lived free of disease. Research, based on data from a long-running U.S. heart-health study, found that the impact of high blood pressure on life expectancy may be more significant than previously estimated. Researchers found that high blood pressure at the age of 50 shaved about 5 years off men's and women's lives. It also caused them to endure 7 more years with cardiovascular disease compared with their peers who had normal blood pressure in middle-age. It's well known that high blood pressure raises the risk of heart disease, stroke and kidney failure, but only a few studies have looked at how blood pressure affects longevity.

Stress reduction Chronic psychological stress is associated with accelerated shortening of the caps, called telomeres, on the ends of chromosomes in white blood cells -- and thus hasten their demise -- according to a report in the Proceedings of the National Academy of Sciences. Telomeres promote chromosome stability. Telomeres shorten with each replication of the cell, and cells cease dividing when telomeres shorten sufficiently. The team investigated the theory that psychological stress affects telomere shortening and thereby contributes to a decrease in longevity. Their study included 39 healthy, premenopausal women who were primary caregivers for a child with a chronic illness, and 19 age-matched mothers of healthy children who served as a comparison "control" group. Stress was measured with a standardized questionnaire, and telomere length was measured in participants' blood samples. Within the caregiving group, the longer that a woman had been a caregiver, the shorter was the length of telomeres. In the 14 women with the highest stress scores, telomeres averaged 3,110 units in length; the 14 with the lowest stress had telomeres that averaged 3,660 units. In adults, telomeres shorten by an average of 31 to 63 units per year, so the scientists estimate that the 550-unit shortening in the high-stress group translates to 9 to 17 additional years of aging.

Mitochondria and acetyl-l-carnitine Decline in mitochondrial function may lead to cellular energy deficits, especially in times of greater energy demand, and compromise vital ATP-dependent cellular operations, including detoxification, repair systems, DNA replication, and osmotic balance. Mitochondrial decay may also lead to enhanced oxidant production and thus render the cell more prone to oxidative insult. In particular, the heart may be especially susceptible to mitochondrial dysfunction due to myocardial dependency on beta-oxidation of fatty acids for energy and the postmitotic nature of cardiac myocytes, which would allow for greater accumulation of mitochondrial mutations and deletions. Thus, maintenance of mitochondrial function may be important to maintain overall myocardial function. Herein, we review the major age-related changes that occur to mitochondria in the aging heart and the evidence that two such supplements, acetyl-l-carnitine (ALCAR) and (R)-alpha-lipoic acid, may improve myocardial bioenergetics and lower the increased oxidative stress associated with aging. We and others have shown that feeding old rats ALCAR reverses the age-related decline in carnitine levels and improves mitochondrial beta-oxidation in a number of tissues studied. However, ALCAR supplementation does not appear to reverse the age-related decline in cardiac antioxidant status and thus may not substantially alter indices of oxidative stress. Lipoic acid, a potent thiol antioxidant and mitochondrial metabolite, appears to increase low molecular weight antioxidant status and thereby decreases age-associated oxidative insult.

Japanese women had a life expectancy of 85.59 years in 2004, making them the world's longest living group for the 20th consecutive year. Japanese men trailed with a life expectancy of 78.64 years, which placed them second for longevity after Icelandic men, who live an average of 78.8 years.

Octogenerian has a baby An 88-year-old Indian farmer has become the father of a baby boy. He says he has sex daily and wants more kids. "I don't want to live to 100 but, as long as I live, I should be able to enjoy sex," said Virmaram Jat, who lives in a village in the Barmer district in the western desert sate of Rajasthan. The prosperous farmer, with a flowing white beard and a weather-beaten face, says he takes long walks every day and has been drinking fresh camel milk since childhood. The paper reported his latest wife -- his third -- is 45 years younger and delivered male twins last month, but only one boy survived. The octogenarian is a vegetarian and has never smoked cigarettes or drunk alcohol.

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Longevity, how to live longer with diet, food, and dietary ...

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Genetics of Longevity in Model Organisms: Debates and ...

BOSTON, Massachusetts (AP) -- A young man climbs from bed, stares into a mirror and glimpses his future.

He has just turned 34. His body is trim, his hair thick and dark. But what's that around his eyes? Those crow's-feet are getting harder to ignore. And do his teeth look a bit ground down by decades of chewing, or is it his imagination?

He will probably repeat the same check tomorrow, and tomorrow, and tomorrow -- about 16,000 more times if he, like the average American, dies at around 80. "I don't think 80 years is long enough. There's a lot of things I want to do," he laments.

But what can he -- or anyone -- do about getting old? He can't stop it, any more than he can dispel rain clouds roiling on the horizon, any more than ancient alchemists could distill a real elixir of immortality.

Or can he?

His name is David Sinclair. He is biologist at Harvard Medical School. His job is to prevent aging.

Catapulted by advances in biotechnology, scores of researchers have begun to pinpoint genes that may prolong human life while delaying its late-stage diseases, frailties and maybe even gray hair and wrinkles. Their remarkable successes in laboratory animals -- like worms that live four times longer than normal -- have already germinated several drug companies. They hope to develop compounds to stretch healthy lifetimes beyond limits once presumed to be fixed.

Some respected researchers envision millions living as long as Jeanne Calment of France, who died at age 122 in 1997. Tom Johnson, a University of Colorado geneticist, thinks people could one day live to 350 years old, spanning the ages like Methuselah and the other biblical patriarchs.

"I am absolutely convinced we are going to be able to extend human life," Johnson says. "This is not science fiction."

Under the best circumstances, a life-prolonging drug could conceivably arise in five years, says longevity guru Cynthia Kenyon, a molecular geneticist at the University of California-San Francisco.

While enthusiastic about distant prospects, some others predict only modest advances for the near future, because aging is such a fundamental and complex process. "I think it would be sensationalist and crazy to think we'd be seeing people living to 120, 130," argues Thomas Perls, a Boston University aging specialist who studies the genetics of centenarians.

In truth, no one knows for sure what can be accomplished or how soon. However, for the first time in human history, an intense and methodical quest is under way to turn off aging with proven science, instead of snake oil.

For centuries, aging has been understood as a scattered, chaotic, inevitable breakdown of the body and its organs. Like a car with too many miles, it eventually wears out. You can keep fixing parts, but others soon break down.

There was special reason for doubt in the genetic approach to slowing aging. Evolutionary theory dictates that we inherited genes that most helped our ancestors reach sexual maturity, not ones that helped or hurt them afterward.

If so, a genetic trigger for aging would be a long shot, except for one thing.

At first, it was more of a biological curiosity. In the 1930s, Cornell University nutritionist Clive McCay discovered that underfed rats live a lot longer than others. Just cut calories by about 30 percent, balance their diet, and they survive about 40 percent longer or more. The technique works in fish, fleas, and other species, and early data suggest it works in monkeys too, say researchers at the University of Wisconsin and the National Institute of Aging.

Underfeeding has revealed a second remarkable power: It keeps animals healthy, largely free of aging ailments like cancer and heart disease. They stay strong and energetic. They even keep more fur.

"On one side, the calorie-restricted mice are jumping, and running around, and looking young," says Stephen Spindler, a biochemist who does such experiments at the University of California-Riverside. "On the other side, the litter mates look old. They're gray, and they have more balding. They move less. It makes me want to go on a diet."

Even if it proved to work in people -- still an open question -- few would likely tolerate such a Spartan diet.

Maybe dieting isn't necessary, though. Researchers suspected that the effects of underfeeding point to some built-in biological switch after all: a set of master genes that can delay aging. Could they be found? And could their effect be mimicked by a drug that boosts or blocks the right proteins, the soldier molecules that do the work assigned by genes?

Kenyon, of the University of California-San Francisco, knew of a microscopic roundworm that, when starved or overcrowded, slips into suspended animation. In this hardened condition known as dauer, it can hold out for months. It would otherwise die within about three weeks.

This state is directed by a gene, daf-2, that controls growth by helping manufacture an insulin-like hormone. Kenyon wondered if worms with disabled variants of this gene might turn into spry, wiggly Methuselahs. In her tests, they did. Similar manipulations worked in flies and mice. A raft of such discoveries in the 1990s helped legitimize the new field of aging genetics.

"Aging had been cast kind of into the trash heap of biology, particularly in molecular terms. There's nothing much you can do about it, so what's the point?" says Kenyon, a 40-something dynamo who talks in a teenager's rapid-fire bursts and gives her age as 150.

Over the past 15 years, researchers have discovered several dozen genes that prolong life significantly in yeast, roundworms, fruit flies and mice. As in underfed animals, they appear to put off not just death, but the hobbling conditions of old age.

Most of these genes carry deadpan scientific monikers: p66shc, ctl-1, Lamin A. Others were mercifully christened in whimsy like age-1, clock, Methuselah, and INDY -- for "I'm Not Dead Yet," a name inspired by a line from a Monty Python movie.

Many longevity genes first tracked in animals have human counterparts. Other genes were first spotted in humans.

Nerve researcher Gabrielle Boulianne, of the University of Toronto, was studying one of them in 1998. She was researching amyotrophic lateral sclerosis, the degenerative nerve condition known as Lou Gehrig's disease. It had been linked to a gene known as SOD1, which treats metabolic waste products. Since fruit flies carry a twin gene, she transplanted and supercharged the human gene in their nerve cells, hoping to develop a research model for the disease.

What happened next was unforeseen: The flies lived an average of up to 40 percent longer. "In some respects, I was shocked," Boulianne says. "That was not the original goal."

In keeping with underfeeding experiments, some of these genes help resist environmental threats, like food shortages, overheating or infection. Some slow down metabolism or boost its efficiency. Others help recondition the body's protein building blocks or reduce the destruction of gene-degrading free radicals. Still others make hormones that control growth and cell division, a process that goes awry in cancer.

Many of these genes, like gatekeepers, open or close access to other genes. At the Massachusetts Institute of Technology, Lenny Guarente -- Sinclair's mentor -- is pursuing a gatekeeper gene common to mice and humans, SIRT1. It is tied to several players implicated in aging: sugar metabolism, hormone signaling, and cellular death.

In theory, such genes can block the chemical messengers that spur aging ailments like cancer, heart disease and Alzheimer's. These researchers dream of one pill that fits all.

"It's a new way in thinking about diseases," says Guarente, a lanky 51-year-old with an impish smile who looks like he may have already found an aging secret and tried it.

Elixir Pharmaceuticals, which he co-founded in Cambridge, Massachusetts, plans to test several drugs in animals. Since its early days in 2001, it has raised $36.5 million and grown to a staff of about 30, according to CEO Edward Cannon.

He acknowledges it's still unclear how to move a longevity drug to market. Given even the paltry human life span now, the thorough testing required by the U.S. Food and Drug Administration would take too long. Cannon says the first longevity drugs might be approved for specific diseases of aging, but prescribed more broadly by some doctors to prolong life.

"It's a great business opportunity," says Xi Zhao-Wilson, CEO of a competitor, Biomarker Pharmaceuticals in Campbell, California. "The market is huge, we know that."

Some executives say their longevity products might be marketed first for pets or as human dietary supplements, allowing makers to skirt full-blown human testing. It's a market where claims are sometimes made on shaky grounds, but the longevity companies say their products would be based on solid science.

Some biologists worry that likely side effects are being undersold already. They say that nearly any drug that alters the workings of a powerful master gene will probably stir up unintended effects. They warn of infertility, sluggish metabolism or weakened immunity.

Longevity researcher Steven Austad at the University of Idaho says all aging genes found so far would do harm "not necessarily apparent in the laboratory."

Yet he felt confident enough to bet a colleague $150, on a lark, that someone born by 2000 will be alive and well in the year 2150. Assuming that person wouldn't be either of them, the two scientists banked their combined $300 to pay the winner's descendants when the bet is decided.

By then, the pot is estimated at $500 million, thanks to something that only gets better with time: compound interest.

Taking Austad's bet was sociologist S. Jay Olshansky, an authority on aging demographics at the University of Illinois-Chicago. "You get many of these gene jockeys grossly exaggerating and extending the work done on invertebrates and other organisms to ... humans," he says. But even he holds great hope for the field in the long run.

Some scientists and scholars say it's already time to start considering how to handle the profound impact long-life drugs would have on society. Will they tack on extra years of sickness to the bonus years of health, overwhelming the medical system? Can society create enough jobs for older workers and support retirees longer?

Political scientist Francis Fukuyama, on The President's Council on Bioethics, says such problems beg for discussion because a proven longevity drug would be "almost impossible to stop."

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You may get your hair color from your fathers side of the family and your great math skills from your mother. These traits are in the genes, so to speak. Likewise, longevity tends to run in familiesyour genetic make-up plays an important role in how you age. You can see evidence of this genetic connection in families with siblings who live into their 90s or families that have generation after generation of centenarians. These long-lived families are the basis for many genetic studies.

Identifying the genes associated with any trait is difficult. First, just locating the gene requires a detailed understanding of the trait, including knowledge of most, if not all, of the contributing factors and pathways related to that trait. Second, scientists must have clear ways of determining whether the gene suspected to have a relationship with the trait has a direct, indirect, or even no effect on that trait.

Identifying longevity genes is even more complex than determining genes for height or hair color, for example. Scientists do not know all the factors and pathways that contribute to longevity, and measuring a genes effect on long-lived animals, including humans, would literally take a lifetime! Instead, scientists have identified hundreds of genes that affect longevity in short-lived animal models, like worms and flies. Not all of these genes promote long life. Sometimes mutating or eliminating a gene increases lifespan, suggesting that the normal function of the gene limits longevity. Findings in animal models point to places for scientists to look for the genes that may influence longevity in humans.

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GENETICS: Is aging in our genes? - nia.nih.gov

Our story began in the 1970s with a young student in a lonely laboratory. So consumed with his work, he barely had time to attend to classes. So advanced, that his education was not found in books, but in the fabric of what makes us human: our DNA. His dedication is now legendary, and his work set in motion countless genetic discoveries, including the Human Genome Project, the first initiative to map all genes in the human genome. Today, Dr. George Church is a recognized giant in genetic science and one of the co-founders of Veritas Genetics. Along with an esteemed group of visionaries and scientists, including a few from Harvard Medical Schools Personal Genome Project, Church and Veritas Genetics have become the leader in genetic sequencing and interpretation. It took 10 years and nearly $3 billion dollars to sequence the first whole human genome. Now, were delivering it into the palm of your hand in a matter of weeks, all for less than half the cost of the average family vacation.

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Veritas Genetics - Committed to disease prevention, early ...

by Ben Best CONTENTS: LINKS TO SECTIONS BY TOPIC

Often we see people who smoke, don't exercise and eat all the wrong foods living to be a ripe old age. People tell us that it doesn't matter whether you smoke or are overweight, what matters is having good genes. Is this true?

The simple answer is that for every elderly person who is overweight, smokes, doesn't exercise, eats the wrong foods and doesn't take supplements there are many more who lived the same lifestyle and are in the cemetery (and who are therefore less visible). There are also many more people the same age who are living a more healthy lifestyle (emphasis on "living") and who are more healthy. Good heredity can protect you from bad living somewhat, but you are better off to live well.

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The longest, largest and most authoritative study on the effects of smoking upon health and longevity has followed the lives of nearly 35,000 British physicians since 1951[BRITISH MEDICAL JOURNAL; Doll,R; 328(7455):1519-1528 (2004)]. Although physicians may not seem representative of the population in general, their health histories and causes of death are very well documented.

Claims have been made that smokers die earlier than nonsmokers due to more risk-taking personalities, rather than because of the effects of tobacco. True enough, heavy smokers (over 25 cigarettes per day) in the study died of accidents, injury and poisoning more than twice as often as nonsmokers (in a couple of cases from fires started while smoking in bed). But these deaths accounted for less than 3% of total mortality.

According to the study, a heavy smoker is about 25 times more likely to die of lung cancer than a nonsmoker. And a light smoker (1 to 14 cigarettes per day) is about 8 times more likely to die of lung cancer. Similarly, a heavy smoker is about 24 times more likely to die of chronic obstructive pulmonary disease than a nonsmoker and a light smoker is about 9 times more likely. A similar relationship is seen for death rates from other forms of cancer and respiratory disease. This close relationship between fatal lung disease and smoking makes it difficult to deny that the smoke is directly damaging to the lungs.

On average, the nonsmokers lived about 10 more years than the smokers. For those born between 1920 and 1929 the death rate between the ages of 35 and 69 for nonsmokers was 15% and for smokers was 43% nearly three times greater. Of course, the smokers who survived beyond age 69 probably had better genes than those who did not, but they undoubtedly suffered more from respiratory disease and other forms of illness than the surviving nonsmokers.

The British physician study results are very similar to a survey of nearly a million American men and women by the American Cancer Society[AMERICAN JOURNAL OF PUBLIC HEALTH; Taylor,DH; 92(6):990-996 (2002)].

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(For more detail, see Health Benefits of Exercise)

Many studies have shown an association between exercise and reduced incidence of heart disease, adult onset diabetes and even cancer. A study of nearly 45,000 male health professionals showed that those who exercised in the highest 25% of intensity had a risk of coronary heart disease that was 70% that seen among the lowest 25%[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Tanasescu,M; 288(16):1994-2000 (2002)]. A study of nearly 22,000 male physicians showed that men who exercised 2 to 4 times weekly had 80% the stroke rate of those who exercised less than once per week[STROKE; Lee,IM; 30(1):1-6 (1999)]. A study of over 72,000 nurses showed that the fifth of women who exercised the most had 66% the stroke risk of the fifth who exercised the least. The middle fifth had 82% of the stroke risk of the fifth who exercised the least25%[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Hu,FB; 283(22):2961-2967 (2000)].

Diabetes increases the incidence of a variety of health conditions, including heart disease, neuropathy, kidney failure, etc. increasing the likelihood of an early death. In many ways diabetes exhibits the features of accelerated aging. "Type2 diabetes" also called "non-insulin-dependent diabetes" was formerly called "adult onset diabetes". But adolescents have increasingly been developing the disease. A Cincinnati study showed a ten-fold increase in adolescent type2 diabetes in the period between 1982 and 1994[THE JOURNAL OF PEDIATRICS; Pinhas-Hamiel,O; 128(5Pt1):608-615 (1996)]. There was not a ten-fold change in genetic makeup of adolescents in that period, but there was a great increase in adolescent obesity. A study of nearly 85,000 nurses concluded that obesity is the single most important factor leading to type2 diabetes in women[NEW ENGLAND JOURNAL OF MEDICINE; Hu,FB; 345(11):790-797 (2001)] (a result which is probably valid for men as well).

A study of nearly 22,000 male physicians showed that those who exercised more than 5times weekly had only 58% the incidence of type2 diabetes as those who exercised less than once per week. Those who exercised two to four times weekly had 62% the diabetes incidence and those who exercised once weekly had 77% the incidence[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Manson,JE; 268(1):63-67 (1992)]. Someone could argue that those who chose to exercise were those who are less likely to get diabetes, but a study which randomly assigned 3,234 non-diabetic persons to exercise at least 150 minutes per week or to not exercise showed those who exercised were only 58% as likely to get type2 diabetes as those who did not[NEW ENGLAND JOURNAL OF MEDICINE; Knowler,WC; 346(6):393-403 (2002)].

Even cancer risk might be reduced by exercise. An extensive review of the literature found a high relationship for both colorectal cancer and breast cancer with lack of exercise[CANCER CAUSES AND CONTROL; McTiernan,A; 9(5):487-508 (1998)]. Breast cancer and colorectal cancer are significantly influenced by diet as well as by exercise. A study in Italy found a correlation between these forms of cancer and the intake of saturated (but not polyunsaturated) fat[ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY; Favero,A; 492:51-55 (1999)].

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(For more detail, see Macronutrients, Dieting and Health)

A study of nearly 40,000 women health professionals found that the fifth who consumed the most dietary fiber had 46% the risk of myocardial infarction and 65% the total cardiovascular disease risk of the fifth consuming the least dietary fiber[JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY; Liu,S; 39(1):49-56 (2002)].

A study of Seventh Day Adventists showed that those who observed a vegetarian diet were at least four times less likely to have high blood pressure than those who ate meat[JOURNAL OF HYPERTENSION; Rouse,IL; 1(1):65-71 (2002)]. About a third of California Seventh Day Adventists are vegetarians, and those vegetarians have been shown to live 9.5 years (men) or 6.1 years (women) longer than other Californians. High blood pressure can cost 4.2 years (men) or 3.2 years (women) and diabetes (which is usually very susceptible to influence by diet) can cost 4.6 years (men) or 8.6 years (women)[ARCHIVES OF INTERNAL MEDICINE; Fraser,GE; 161(13):1645-1652 (2001)]. A prospective study of over half-a-million people found elevated mortality, cancer mortality and cardiovascular disease mortality in those who at red meat and processed meat (sausage, hot dogs, etc.)[ARCHIVES OF INTERNAL MEDICINE; Sinha,R; 169(6):562-571 (2009)].

The literature abounds with evidence that diets rich in fruits and vegetables reduce the risk of cancer and cardiovascular disease[JOURNAL OF POSTGRADUATE MEDICINE; Heber,D; 50(2):145-149 (2004)]. Diet certainly has an influential effect on longevity which is separable from heredity.

Caloric Restriction with Adequate Nutrition (CRAN) dramatically extends the maximum lifespan of laboratory animals. Rats, mice and hamsters experience maximum lifespan extension from a diet which contains 4060% of the calories (but all of the required nutrients) which the animals consume when they can eat as much as they want. Mean lifespan is increased over 50% and maximum lifespan is increased over 30%. There is evidence that humans on CRAN experience similar benefits. The experimental animals in these studies are compared to genetically-matched controls which eat freely and experience no life extension benefits. The dramatic diffenece in lifespan is due to diet, not genes.

The composition of protein, carbohydrate and fat in the diet can also significantly affect health and longevity. For details on this subject, see my essay Macronutrients, Dieting and Health.

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(For more detail, see Nutraceuticals Topic Index )

What about nutritional supplements? Poor nutrition is common, especially in the elderly. Supplements consisting of recommended dietary allowances of nutrients (plus extra VitaminE & beta-carotene) significantly improved the immune status of elderly subjects[THE LANCET 340:1124-1127 (1992)]. In fact, a randomized, double-blind placebo-controlled study of 200IU supplementation with alpha-tocopherol in persons over 65 years of age showed a 20% reduction in incidence of the common cold[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Meydani,SN; 292(7):828-836 (2004)].

In 1996 the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION published the results of a multi-center, double-blind, randomized, placebo-controlled cancer prevention trial based on 200g/day selenium or placebo to 1,312 patients over a mean period of 4.5years[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Clark,LC; 276(24):1957-1963 (1996)]. The study reported a 50% decrease in total cancer incidence as well as a 63% reduction in prostate cancer, a 58% reduction in colorectal cancer and a 48% reduction in lung cancer. Only 6 of the 1,312 subjects had selenium blood levels below that achievable by the RDA prior to supplementation. Not only was this study a powerful refutation of the claim that dietary supplements are of no benefit, but its results were so impactful that it would be unethical for anyone to repeat it. After extensive scrutiny of the data only the evidence for reduction of prostate cancer is now accepted as statistically significant (for a 42% reduction in prostate cancer). The data still shows a total cancer mortality reduction of 51%[CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION; Duffield-Lillico,AJ; 11(7):630-639 (2002)].

It is worth noting the recent efforts of Dr. Bruce Ames to promote the use of supplements. Bruce Ames is most famous for the "Ames Test" which has allowed researchers to use bacteria rather than lab animals to screen for potential cancer-causing agents thus expediting the screening process. Dr. Ames says that it is unreasonable to expect that everyone (particularly the poor) is going to eat the recommended five servings of fruits and vegetables every day. He not only advocates a general vitamin and mineral supplement as an "insurance policy" to ensure getting the recommended minimums, but advises that recommended minimums are not sufficient to provide maximum protection from disease. And he notes the regenerative potential of taking supplements that combine lipoic acid with acetyl-L-carnitine[EMBO REPORTS; Ames,BN; 6(SpecNo):S20-S24 (2005)].

AntiOxidants and other supplements are excessively disparaged by some biogerontologists on the grounds that they do not increase maximum lifespan. But significantly increasing average age of death can be a gain in both life and health. The Nutraceuticals section of this website provides a great deal of evidence that nutritional supplements can improve health and thereby increase average lifespan ("square the curve").

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In Western countries, females live about 10% longer than males. Males have 4times as much oxidative DNA damage as females, presumably because females have more MnSOD and glutathione peroxidase[FREE RADICAL BIOLOGY & MEDICINE; Borras,C; 34(5):546-552 (2003)]. A 2002 study of centenarians in the United States found that female siblings were 8times more likely to reach age100 than cohorts born the same year and male siblings were 17times for likely to become centenarians themselves[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Perls,TT; 99(12):8442-8447 (2002)]. Mothers of persons who lived to at least 110years ("supercentenarians") were nearly six times more likely to have lived to age90 than females in the general population[JOURNAL OF GERONTOLOGY; Perls,T; 62A(9):1028-1034 (2007)]. Studies of centenarian populations have found quite a number of longevity-associated genotypes[PLoS GENETICS; Martin,GM; 3(7):e125 (2007)].

Children of older fathers (within the age range 25 to 45) were found to have longer telomeres and greater resistance to mortality from aging-associated diseases[AGING CELL; Unryn,BM; 4(2):97-101 (2005)]. A ten-year study of Danish twins aged 73-94 found a positive correlation between leucocyte telomere length and expected lifespan[AMERICAN JOURNAL OF EPIDEMIOLOGY; Kimura,M; 167(7):799-806 (2008)]. Studies of sperm from young(<30years) and old(>50years) donors found that sperm telomerase length increases with age[PLOS GENETICS; Kimura,M; 4(2):e37 (2008)].

Male sperm are produced throughtout life, whereas a woman typically produces few, if any, new egg cells during her reproductive years. For this reason, a mother typically passes about 14mutations to her offspring, whereas a father will pass about 40mutations at age20 and 80mutations at age40. Mutations in the father increase exponentially with age, doubling about every 16.5years[NATURE;Kong,A; 488:471-475 (2012)]. Risk of diseases such as autism and schizophrenia in offspring rise with increasing age of the father[Ibid.].

The cause of death for a sample 143 people over the age of 60 with shorter telomeres was found to be several times greater for heart disease and infectious diseases, but not for cancer[THE LANCET; Cawthon,RM; 361:393-395 (2003)]. Another study showed a significant correlation between telomere shortening and cognative impairment in elderly subjects[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Canela,A; 104(12):5300-5305 (2007)]. Yet another study found an inverse relationship between telomere length and pulse pressure, indicating a possible direct relationship between vascular aging and telomere length[HYPERTENSION; Jeanclos,E; 36(2):195-200 (2000)]. In a cohort of coronary artery disease outpatients the rate of telomere shortening was inversely related to blood levels of omega-3 polyunsaturated fatty acids[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Farzaneh-Far,R; 303(3):250-257 (2010)]. Higher levels of oxidative stress due to environmental factors increase the rate of telomere shortening[TRENDS IN BIOCHEMICAL SCIENCES 27(7):339-344 (2002)]. Psychological stress may be one of the environmental factors[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Epel,ES; 101(49):17312-17315 (2004)]. A study of 175 elderly Swedish twin-pairs found that the twins with the shortest telomeres (75% of the cohort) had 3times the risk of death compared to the 25% with the longest telomeres[AGING CELL; Bakaysa,SL; 6(6):769-774 (2007)].

Identical twins (monozygotic twins) have the same heredity (identical genes), so differences in the health and longevity of identical twins can only be due to environmental factors. Of course, identical twins typically have similar environments. Fraternal twins are also born together, are no closer genetically than other siblings, and have environments which are probably as similar as those shared by identical twins. Thus, comparing identical twins with fraternal twins can be a way of determining which effects are due to heredity and which are due to lifestyle (environment).

A study of Scandinavian twins found that if a female lived to be at least 92years, a fraternal twin had 1.57 the chance of doing so, and an identical twin was 2.5times more likely to do so than other females. For males, a fraternal twin was 1.76times as likely to reach 92 and an identical twin was 4.83times as likely[HUMAN GENETICS; Hjelmborg,J; 119(3):312-321 (2006)].

Both fraternal and identical twins show correlated levels of the inflammatory cytokines Tumor Necrosis Factor-alpha(TNF) and IL6 which play a role in diabetes and metabolic syndrome indicative of the influence of a common environment, including the intrauterine environment. Nonetheless, elderly twins show a strong genetic component to their plasma TNF levels[DIABETOLOGIA; Grunnet,L; 49(2):343-350 (2006)]. A study of 80-year-olds found that serum IL6 levels predicted mortality for both males & females, but TNF only predicted mortality for males[CLINICAL &; EXPERIMENTAL IMMUNOLOGY; Bruunsgaard,H; 132(1):24-31 (2003)]. But another study found serum TNF to predict mortality in centenarians, whereas IL6, IL8 and CRP did not[AMERICAN JOURNAL OF MEDICINE; Bruunsgaard,H; 115(4):278-283 (2003)].

Female centenarians are significantly more likely to have a gene that reduces IGF1 receptor signalling[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Suh,Y; 105(9):3438-3442 (2008)]. Two copies of a FOXO3A allele tripled the odds of becoming a centenarian in a Japanese-American cohort[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Willcox,BJ; 105(37):13987-13992 (2008)].

A long-term study of twins in Denmark showed that when one fraternal twin had a fatal stroke, there was a 10% chance that the other fraternal twin would die of stroke. But for identical twins there was an 18% chance that the second twin would also die of a stroke[STROKE; Bak,S; 33(3):769-774 (2002)]. The fact that identical twins (who have exactly the same genes) would be nearly twice as likely to have a stroke as fraternal twins (who are no closer genetically than any brother or sister) indicates that heredity does play a role in the likelihood of having a stroke. Nonetheless, the fact that when one of two genetically identical twins has a stoke that there is a less than 20% chance that the second genetically identical twin will have a stroke indicates that at least 80% of the chance of having a stroke is due to environmental (lifestyle) factors.

The Framingham Longevity Study showed that age at death can be predicted much better by Coronary Heart Disease (CHD) risk factors than risk factors for stroke or cancer[JOURNAL OF CLINICAL EPIDEMIOLOGY; Brand,FN; 45(2):169-174 (1992)]. A study of nearly 21,000 Swedish twins[JOURNAL OF INTERNAL MEDICINE; 252(3):247-254 (2002)] showed that when one male twin died of CHD there was a 57% likelihood that the other male twin would also die of CHD. Insofar as only about 20% of males normally die of CHD (roughly half of all male deaths due to cardiovascular disease are due to CHD), 57% represents nearly 3 times the frequency that would be expected between randomly selected pairs of men. Although this represents a significant role for heredity in CHD death for men, the fact that 43% of male twins die of causes different from the CHD that killed the first twin indicates a significant role for lifestyle in causing CHD death.

For female twins only in 38% of cases did the second twin die of CHD when the first twin had died of CHD. This would seem to indicate that for women, lifestyle rather than heredity more strongly influences the chance of dying from CHD than is the case for men. However, the study noted that the older twins were when they died, the less likely it would be for both twins to die of the same cause. In other words, the longer you live, the more your cause of death will be determined by your lifestyle rather than by your heredity. Women normally live longer than men, so by dying at a greater age their causes of death are more influenced by lifestyle and less influenced by heredity than is the case for men. If men had lived longer, we would expect greater differences in cause of death between the male twins.

Divergence of twins with age is not only evident in lifestyle factors such as smoking, exercise, diet and environment, but in gene expression. A study which compared 3-year-old identical twins with 50-year-old identical twins found that the younger twins were very epigenetically similar, whereas the older twins were very distinct in epigenetic expression[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Fraga,MF; 102(30):10604-10809 (2005)]. A study on mice showed that alterations in epigenetic expression with age may be up to two orders of magnitude greater than somatic mutations[GENETICS; Bennett-Baker,PE; 165(4):2055-2062 (2003)].

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Good genes do make a difference in being healthy and living long, but lifestyle choices usually make a bigger difference. And the longer we life, the more our remaining longevity depends upon our lifestyle rather than on our genes. The choice is not between quantity (long life) and quality (good health), because good health is usually a requirement for living long. Whether your genes are good or bad, you will probably be more healthy as well as live longer by not smoking, by exercising and by eating a good diet (which can be augmented by supplements).

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Is Longevity Entirely Hereditary? - BEN BEST

Healthy aging and longevity in humans are modulated by a lucky combination of genetic and non-genetic factors. Family studies demonstrated that about 25% of the variation in human longevity is due to genetic factors. The search for genetic and molecular basis of aging has led to the identification of genes correlated with the maintenance of the cell and of its basic metabolism as the main genetic factors affecting the individual variation of the aging phenotype. In addition, studies on calorie restriction and on the variability of genes associated with nutrient-sensing signaling, have shown that ipocaloric diet and/or a genetically efficient metabolism of nutrients, can modulate lifespan by promoting an efficient maintenance of the cell and of the organism. Recently, epigenetic studies have shown that epigenetic modifications, modulated by both genetic background and lifestyle, are very sensitive to the aging process and can either be a biomarker of the quality of aging or influence the rate and the quality of aging.

On the whole, current studies are showing that interventions modulating the interaction between genetic background and environment is essential to determine the individual chance to attain longevity.

The research on aging, and in particular the search for the determinants of successful aging and longevity, has been continuously growing in the last decades also due to the social and medical burden correlated to the continuous increase of lifespan in western countries and the consequent grow of the elderly population. One of the main questions in this field is the correlation between the genetic background and lifestyle in determining the individual chance of a delayed aging (possibly without age-related diseases and disabilities) and longevity. The results obtained by biogerontologists in these years, which highlighted most of the biological and biochemical mechanisms involved in the aging process, allowed to better understand such correlation. This has brought to elaborate important strategies focused on possible interventions to improve lifestyle in order to increase the chance to attain longevity by modulating the basic molecular mechanisms of aging.

Before the 1990ies it was largely spread the idea that aging is ineluctable and that genetics does not control it. It was important, in this view, the idea that aging occurs after reproduction, and then there is no need, but also no opportunity, for selection to act on genes that are expressed during this late period of life [1].

The researcher who pioneered the genetics of aging and longevity was Tom Johnson, who studied groups of C. elegans where he was able to separate long living individuals from short living subjects. The analysis of hybrids obtained from different strains of C. elegans, allowed to estimate that the heritability of life-span was between 20 and 50% [2, 3]. Subsequently, he started the analysis of different mutants and, with M. Klass, found a number of mutants with longer lifespan. Subsequently, Tom Johnson found out that most of the mutants with long lifespan had mutations in the age1 gene [4]. This gene turned out to be the catalytic subunit of class-I phosphatidylinositol 3-kinase (PI3K).

The studies of Johnson clearly demonstrated that genetic variability could indeed affect lifespan. This triggered many studies in model organisms in order to disentangle the different biochemical pathways which could affect lifespan, and to highlight the genes coding for the proteins involved in such pathways. In particular, yeast, C. elegans, drosophila and mice were analyzed and this highlighted numerous genes which could affect lifespan if mutated (for an updated list of these genes see http://genomics.senescence.info/genes/models.html). Most of these genes are related to the maintenance of the integrity of the cell (especially the integrity of DNA). In C. elegans, however, some of the main genes which have been found to modulate lifespan (daf2, daf16) are related to the ability to enter the dauer status [5, 6], that is a quiescent status (usually entered in case of nutrient deprivation) with a minimum energy expense, which causes an arrest of the reproduction process and allows the organism to live longer expecting for the availability of nutrients. This suggested that longevity can be attained by means of an efficient maintenance of the cell but also by diverting resources from reproduction to self maintenance, in line with previous findings that dietary restriction can extend lifespan. After the characterization of these genes in C. elegans, it was found that in mice the ortholog of daf16 (FOXO) could affect lifespan. In mammals, FOXO is correlated to the Insulin/IGF1 axis which is stimulated by nutrient availability and, through FOXO, promotes protein synthesis [711].

It is of note that some Authors suggested these molecular mechanisms modulating lifespan could be due to a pleiotropic effect of genes which have evolved for different purposes (such as the genes in the IGF-1 pathway which have evolved to face presence/absence of nutrients) but can, ultimately affect lifespan; others proposed that some genes may have evolved to program aging and avoid immortality, as this would hamper the continuous substitution of old subjects with new, younger, ones [12, 13].

It was obviously inevitable that the research of the genetic basis of longevity turned to human beings and investigated whether the common genetic variability of human populations could affect inter individual differences in lifespan but also whether the genes found to prolong lifespan in model organisms, on turn, were correlated to human lifespan.

As to the first question (does common genetic variability affect lifespan, and in particular does it affect longevity?), this has been studied by two approaches. The first one was the reconstruction of the sibships of long-lived subjects [14, 15] and the comparison of their survival curves with those of the birth cohorts born in the same geographical area. This approach demonstrated that brothers and sisters of the long-lived subjects had a clear survival advantage (at any age) with respect to the general population. The second approach, with intrafamily controls, was started in order to distinguish the genetic from the familiar effect. Montesanto et al. [15] compared the survival function of brothers of centenarians with those estimated for their brothers in law, that is with the men who married their sisters; these men were supposed to share with the brothers of the long lived subjects the familiar environment. By using this second approach, it has been found that the survival advantage of siblings of long-lived subjects was not completely shared by their brothers in law, despite they shared the same environment for most of their life. This suggested that beyond the family environment, there are genetic factors influencing survival and, consequently, lifespan. Interestingly, in this study, the survival curve of the sisters of long-lived subjects did not differ from the one of sisters in law, suggesting that the genetic component does explain lifespan in men more than in women. The genetic component of lifespan in humans has also been analyzed by comparing the age of death of monozygotic and dizygotic twins. This has allowed to estimate that about 25% of the variation in human longevity can be due to genetic factors and indicated that this component is higher at older ages and is more important in males than in females [1618].

In parallel to these studies, many researches have been carried out to search the genetic variants responsible of modulating human longevity. Most of them were carried out by a case/control approach, by comparing the frequency of specific polymorphisms in long-lived subjects and in younger geographically matched controls. The rationale of this study design is that as the population ages, alleles favorable for survival will be present at higher frequency among long-living people, while unfavorable alleles will be eliminated [1921]. The candidate genes analyzed by this approach were either genes involved in age-related diseases (such as APOE, which had been observed to be involved in the predisposition to Alzheimer Disease and other age-related cognitive impairments), or genes implicated in pathways related to longevity in studies with model organisms (IGF-1, FOXO, Sirtuins) [2225]. This study design has indeed led to find numerous polymorphic genes the variability of which affects longevity. However, each of these polymorphisms turned out to explain only a very small fraction of the longevity variability. Indeed high-throughput Genome-wide analyses, which have recently been carried out have identified many genes positively associated with longevity but only a very few ones could hold multiple test significance and successfully replicated in different studies and across different populations [2629]. Population stratification and inadequate sample sizes are among the main plausible explanations [30]. The adoption of innovative study design and the development of new statistical and computational tools for effective processing of genetic data arising from high-throughput DNA technologies will help to better understand the complex genetic architecture underlying human longevity [31, 32].

A new way of looking at the genetic data has been proposed by Raule et al. [33] who analyzed the complete sequences of mitochondrial DNA from long-lived subjects coming from different areas of Europe. The availability of complete sequences allowed to evaluate for the first time the cumulative effects of specific, concomitant mitochondrial DNA (mtDNA) mutations, including those that per se have a low, or very low, impact. The analysis indicated that the presence of single mutations on mtDNA complex I may be beneficial for longevity, while the co-occurrence of mutations on both complexes I and III or on both I and V might lower the individuals chances for longevity. Previous analyses on single mutations falling on complex I (either specific mutations or mutations defining groups of haplotypes) had given contrasting results, showing association with longevity in some cases but not in others. It is likely that positive results were obtained in populations were mutations on complex I were not associated with mutations on complex III or V, while negative results were obtained in populations with high prevalence of mtDNA haplotypes carrying mutations on complex I in association with mutations in complex III and V. This approach confirmed that most of the genetic variants have a very limited effect on longevity, and that only their cumulative effect can give a consistent appreciable effect and suggests that a limit of previous analyses has been to search for single mutations instead of cumulative effects. On the other hand, it is very difficult to think of using such approach, which has been successful for mitochondrial DNA, on genomic DNA unless small fractions (or specific regions harboring genes involved in relevant pathways) are analyzed.

On the whole, the genetic association studies suggested that, also in humans, mutations in genes correlated with the maintenance of the cell and of its basic metabolism are essential in modulating lifespan. Indeed, genes involved in DNA repair [34], telomere conservation [3537], heat shock response [38, 39], and the management of free radicals levels [33, 40] were found to contribute to longevity or, in case of reduced functionality, to accelerated senescence (cellular aging) and the consequent organism aging. In addition, as suggested by the studies in mice, the pathways involved in nutrient-sensing signaling and in regulating transcription, such as IGF-1/insulin axis [41] and TOR (target of rapamycin) [42] showed to be involved in modulating human longevity. Besides these genes involved in cellular maintenance/metabolism and senescence, concurrent efforts, especially from clinical studies, also showed that genes implicated in important organismal process may have a strong impact on aging and longevity. For instance genes involved in lipoprotein metabolism (especially APOE), cardiovascular homeostasis, immunity, and inflammation have been found to play an important role in aging, age-related disorders, and organism longevity [4346].

Life expectancy at birth has been increasing for most of the last century in western societies, thanks to the continuous amelioration of medical assistance, to the improvement of the environment (in particular clean, safe water and food), and to the improvement of nutrients. For instance, in Italy life expectancy went from 29years in 1861 to 82 in 2011 (Table

reports the evolution of this data in women and men). Similarly, the extreme longevity has been growing in these years. Indeed, the number of centenarians (still in Italy) remarkably increased from 165 in 1951 to more than 15000 in 2011. These results have been attained first by a dramatic reduction of infectious diseases, which, on turn, has dramatically reduced infantile mortality, but also mortality in adult age. In fact, in 2011 less than 10% of deaths occurred in subjects under 60years of age, while the corresponding figures were 74% in 1872, 56% in 1901 and 25% in 1951. However, in the last decades, the continuous extension of lifespan was mainly due to the improvement of medical assistance with respect to age-related diseases, especially Cardiovascular Diseases and Cancer, which allowed to increase lifespan of 5years in the last 2 decades and of 2years in the last 10years (data from

and

).

Evolution of lifespan expectancy in Italy from 1861

1861

28

29

29

1871

30

31

30

1881

35

35

35

1891

38

39

38

1901

43

43

43

1911

46

46

46

1921

48

50

49

1931

53

56

55

1941

55

58

56

1951

63

67

65

1961

67

72

69

1971

69

75

72

1981

71

78

75

1991

74

80

77

2001

77

83

80

2011

79

84

82

These data clearly show that environmental factors have a very strong impact on lifespan and on longevity in humans. However, the extension of lifespan that there has been in the last decades have not been accompanied by a similar extension of healthy lifespan. Indeed, in most cases this lifespan extension is due to the chronicit of the age-related diseases. This has brought the community of biogerontologists to study interventions, possibly modulated on the knowledge emerged from the studies on the genetic and biomolecular basis of longevity, to extend not only lifespan but also healthy lifespan, or, with a new word, healthspan. In fact, model organisms with mutations that extend lifespan have a healthy life also when they are old. This suggested that health span extension could be attained by targeting (stimulating or silencing) the genes, which had been highlighted to be involved in life extension in both model organisms and humans [47]. In support of this hypothesis, it has been reported that dietary restricted mice, which live much longer and show a very delayed aging phenotype than mice fed at libitum, at old age have an expression pattern very different from mice of the same age for a number of genes correlated with life extension, such as those related to DNA repair, stress response, immune response and others [48, 49]. Thus, dietary restriction can trigger a molecular-genetic response which postpones aging and age-related phenotypes. This has brought to search for drugs or interventions which may act on these mechanisms without the side effects of calorie restriction. Among the most important interventions which have been considered in this context, we may name the protein restriction, the use of drugs targeting different genes of IGF-1 axis or of the FOXO/TOR pathway [47]. In addition, these studies have allowed to reconsider previous data on some areas characterized by exceptional longevity (such as Okinawa, Sardinia and Calabria) which are characterized by traditional ipoproteic diets, such as the Mediterranean diet [5053]. In these cases, then, the environment, that is the traditional diet, has allowed to stimulate the molecular mechanisms which can increase life span.

Among the several changes that occur with the aging process, in the last decade Epigenomics has attracted the interest of many researchers. This was mainly due to the fact that epigenetic modifications summarizing, at least in part, the interaction between the individual genetic background and lifestyle characteristics, should be potentially able to capture part of the unexplained susceptibility observed today for complex diseases (the so-called missing heritability problem).

Starting from the pioneeristic observations that epigenetic modifications affect not only the aging process but also its quality (successful aging) [54], EpiGenome-Wide Association Studies identified hundreds of sites spread along the entire genome in which methylation levels change between oldest old and younger subjects. In particular, Horwat and co-workers, on the basis of the methylation levels of 353 CpG units, formulated a mathematical model, the so-called epigenetic clock, that showed some important properties [55]. First, it was able predict the chronological age of a subject starting from the methylation level of several cells and tissues of his body. Second, it represents one of the most accurate biomarker of age (also superior to the estimates obtained from the telomere length). Third, using methylation levels of blood and brain tissues from subjects affected by Down syndrome, it showed that an accelerated aging occur in such a syndrome [56]. Fourth, it was able to predict all-cause mortality also after adjusting for traditional risk factors [57]. Finally, when it was used to estimate the biological age of several tissues from supercentenarians, it has been demonstrated that brain and muscle represent the youngest tissues of these exceptional individuals [58].

However, even if the cause-effect relationship between methylation process and aging is still not clear, the potential applications of this discovery are very wide, ranging from detailed monitoring of changes occurring with age within individual systems or organs (muscle, brain, etc.) to forensic purposes. For this and several other reasons, future advances in this field could help the understanding of the complex physiology of aging, lifespan and age-associated diseases.

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Human longevity: Genetics or Lifestyle? It takes two to ...

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Posted on April 9, 2014 by Dan Buettner

By Dan Buettner

Life expectancy of an American born today averages 78.2 years. But this year, over 70,000 Americans have reached their 100thbirthday. What are they doing that the average American isnt (or wont?)

To answer the question, we teamed up with National Geographic to find the worlds longest-lived people and study them. We knew most of the answers lied within their lifestyle and environment (The Danish Twin Study established that only about 20% of how long the average person lives is determined by genes.). Then we worked with a team of demographers to find pockets of people around the world with the highest life expectancy, or with the highest proportions of people who reach age 100.

We found five places that met our criteria:

We then assembled a team of medical researchers, anthropologists, demographers, and epidemiologists to search for evidence-based common denominators among all places. We found nine:

1. Move NaturallyThe worlds longest-lived people dont pump iron, run marathons or join gyms. Instead, they live in environments that constantly nudge them into moving without thinking about it. They grow gardens and dont have mechanical conveniences for house and yard work.

2. Purpose. The Okinawans call it Ikigai and the Nicoyans call it plan de vida; for both it translates to why I wake up in the morning. Knowing your sense of purpose is worth up to seven years of extra life expectancy

3. Down Shift Even people in the Blue Zones experiencestress. Stress leads to chronic inflammation, associated with every major age-related disease. What the worlds longest-lived people have that we dont are routines to shed that stress. Okinawans take a few moments each day to remember their ancestors, Adventists pray, Ikarians take a nap and Sardinians do happy hour.

4. 80% Rule Hara hachi bu the Okinawan, 2500-year old Confucian mantra said before meals reminds them to stop eating when their stomachs are 80 percent full. The 20% gap between not being hungry and feeling full could be the difference between losing weight or gaining it. People in the Blue Zones eat their smallest meal in the late afternoon or early evening and then they dont eat any more the rest of the day.

5. Plant Slant Beans, including fava, black, soy and lentils, are the cornerstone of most centenarian diets. Meatmostly porkis eaten on average only five times per month. Serving sizes are 3-4 oz., about the size of deck or cards.

6. Wine @ 5 People in all Blue Zones (except Adventists) drink alcohol moderately and regularly. Moderate drinkers outlive non-drinkers. The trick is to drink 1-2 glasses per day (preferably Sardinian Cannonau wine), with friends and/or with food. And no, you cant save up all weekend and have 14 drinks on Saturday.

7. Belong All but five of the 263 centenarians we interviewed belonged to some faith-based community. Denomination doesnt seem to matter. Research shows that attending faith-based services four times per month will add 4-14 years of life expectancy.

8. Loved Ones FirstSuccessful centenarians in the Blue Zones put their families first. This means keeping aging parents and grandparents nearby or in the home (It lowers disease and mortality rates of children in the home too.). They commit to a life partner (which can add up to 3 years of life expectancy) and invest in their children with time and love (Theyll be more likely to care for you when the time comes).

9. Right TribeThe worlds longest lived people choseor were born intosocial circles that supported healthy behaviors, Okinawans created moaisgroups of five friends that committed to each other for life. Research from the Framingham Studies shows that smoking, obesity, happiness, andeven loneliness are contagious.So the social networks of long-lived people have favorably shaped their health behaviors.

To make it to age 100, you have to have won the genetic lottery. But most of us have the capacity to make it well into our early 90s and largely without chronic disease. As the Adventists demonstrate, the average persons life expectancy could increase by 10-12 years by adopting a Blue Zones lifestyle.

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Power 9 - Blue Zones

Whether your father, mother or siblings have had heart disease may seem like the most important predictor of your own chances of a heart attack. Not so says a large Swedish study published in the Journal of the American College of Cardiology in 2014. In fact, it showed that 5 specific lifestyle factors like eating right, regular exercise and quitting smoking can combine to prevent 80% of first heart attacks.

The researchers, from the Karolinska Institute in Stockholm, set out to determine to what degree healthy habits individually - or in concert - help adults avoid a future heart attack, or myocardial infarction.

Rates of coronary heart disease have dropped in many parts of the world, write the authors, thanks to advances in medications that work to fight high blood pressure and lower cholesterol. Since huge populations are at risk of cardiovascular disease, however, the use of prescription drugs - with their own risks of side effects and significant cost if taken over the long term - are not an effective wide-scale preventative strategy, argue the researchers. They write that their own past research on women and that of other scientists on both genders shows lifestyle changes can dramatically cut heart attack risk.

What the study examined: Men between the ages of 45 and 79 were recruited in 1997, and surveyed about their eating and activity habits, along with data including their weight, family history of heart disease, and level of education.

A total of 20,721 men without any history of cardiovascular disease, cancer, or diabetes were then tracked over an 11-year period.

Five diet and lifestyle factors were examined: diet, smoking habits, alcohol consumption, belly fat and daily activity level.

What the researchers discovered: Each of the five lifestyle habits or conditions was found to offer its own individual benefit in preventing a future heart attack.

The best odds were found among men adhering to all five - reaping an 80% reduction in heart attack risk - although only 1% of the study population was in this category.

Here's how the habits ranked according to heart attack protection:

1. Quitting smoking (36% lower risk): Consistent with extensive previous research, quitting smoking is one of the top longevity-threatening habits you should abandon. In this Swedish trial, men who had either never smoked, or quit at least 20 years prior to the beginning of the study enjoyed a 36% lower chance of a first heart attack.

This jives with findings of many previous investigations including the Million Women Study in the UK, in which almost 1.2 million women were tracked over a 12-year period. That longitudinal research found that quitting by the age of 30 or 40 reaped an extra 11 years of life on average, thanks not only to fewer heart attacks, but less cancer and respiratory disease as well.

2. Eating a nutritious diet (20% lower risk): Again, no surprise that a healthy plant-based diet can help ward off a heart attack (and other age-related diseases like diabetes and cancer). The Swedish study characterized a healthy diet using the Recommended Food Score from the National Health and Nutrition Examination Survey (NHANES) in the US, which is "strongly predictive of mortality" and includes the following:

Those subjects who followed these guidelines most closely had a 20% lower risk of a first heart attack, even if they also ate foods from the "non-recommended" list such as red and processed meat, refined cereals and sweets.

3. Getting rid of belly fat (12% lower risk): Increasingly, epidemiologists are finding waist circumference and waist-to-hip ratio to be a better predictor of ill health than sheer body weight, especially when it comes to abdominal fat that surrounds your internal organs (visceral fat) and not just the pudge that sits under the skin of your belly making your waistband too tight.

Indeed, subjects in this Swedish study whose waistlines measured less than 95 cm (about 38") over the course of the trial, had a 12% lower risk of a first heart attack compared with men with more belly fat.

4. Drinking only in moderation (11% lower risk): In this study, drinking in moderation cut the risk of a first heart attack by about 11%. This is in line with very consistent evidence that consuming alcohol in moderation reduces the risk of cardiovascular disease, including heart attacks and stroke.

Still, the researchers offer certain reservations about alcohol's benefits, since as soon as consumption goes beyond light-to-moderate intakes of 1-2 drinks per day, there are far more hazards than benefits to health in the form of heart disease, cancer and accidents.

To recap: people who drink in moderation may be healthier than teetotalers, but only if they drink in moderation.

5. Being physically active (3% reduction in risk): Men who walked or cycled 40 minutes per day, and exercised at least one hour per week were found to have a 3% lower risk of a first heart attack in this study. That number is surprisingly low, considering other evidence that exercise is very beneficial for heart health. Still, exercise has such strong benefits not only for your cardiovascular system, but towards strengthening your bones, your respiratory system, helping ward off dementia and also stress relief (not to mention avoiding the hazards of sitting still), it should not be considered a fringe health strategy. The more you move, the better.

Wait - didn't this study just look at healthy men? These male subjects were all free of disease when the study launched in the late 1990s. A separate analysis was conducted among more than 7,000 men with hypertension and high cholesterol in 1997, which found that the risk reduction of each healthy behavior was similar to that of men without either condition.

Bottom line: Unlike your genetic makeup, diet, exercise and whether or not you smoke are all within your control; in science jargon, "modifiable lifestyle factors". Such changes may not always be easy to implement, but it can be inspiring to discover that what you do each day can play a greater role in determining your chances of a first heart attack than what you inherit.

In this large study, 86% of first heart attacks were avoided by the small proportion of men who adhered to all 5 healthy habits, regardless of family history of cardiovascular disease. Generalized to the greater population, that means 4 out of 5 first heart attacks might be prevented with straightforward and manageable lifestyle changes.

Get motivated to build healthy habits:

Sources:

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Summary: Researchers have identified a series of genes that could modulate the effect of mood and the response to stress on lifespan.

Source: Indiana University.

The visible impacts of depression and stress that can be seen in a persons face, and contribute to shorter lives, can also be found in alterations in genetic activity, according to newly published research.

In a series of studies involving both C. elegans worms and human cohorts, researchers from the Indiana University School of Medicine and the Scripps Research Institute have identified a series of genes that may modulate the effects of good or bad mood and response to stress on lifespan. In particular, the research pointed to a gene known as ANK3 as playing a key role in affecting longevity. The research was published May 24, 2016 in the journal Molecular Psychiatry.

We were looking for genes that might be at the interface between mood, stress and longevity, said Alexander B. Niculescu III, M.D., Ph.D., professor of psychiatry and medical neuroscience at the IU School of Medicine. We have found a series of genes involved in mood disorders and stress disorders which also seem to be involved in longevity.

Our subsequent analyses of these genes found that they change in expression with age, and that people subject to significant stress and/or mood disorders, such as people who completed suicide, had a shift in expression levels of these genes that would be associated with premature aging and reduced longevity said Dr. Niculescu, who is also attending psychiatrist and research and development investigator at the Indianapolis Veterans Affairs Medical Center.

The research began with studies in C. elegans, a worm widely used in life sciences research. An earlier study by one of the study co-authors, Michael Petrascheck, Ph.D., of the Scripps Research Institute, found that exposing C. elegans to the antidepressant mianserin, which is used to treat mood and stress disorders, extended the animals lifespan.

In the Molecular Psychiatry study, the researchers methodically conducted a series of analyses to discover, prioritize,

Adding genes that had scored nearly as high as ANK3 in the Convergent Functional Genomics analysis to create a panel of biomarkers showed similar but somewhat stronger results, particularly among those who had committed suicide. NeuroscienceNews.com image is for illustrative purposes only.

The authors said that these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and lifespan, that may be biomarkers for biological age as well as targets for personalized preventive or therapeutic interventions.

About this neuroscience research article

Additional investigators contributing to the research were Sunitha Rangaraju, Daniel R. Salomon and Michael Petrascheck of the Scripps Research Institute; Daniel F. Levey, Kwangsik Nho, Nitika Jain, Katie Andrews, Helen Le-Niculescu and Andrew J. Saykin of the Indiana University School of Medicine.

Funding: The research was supported by two National Institutes of Health Directors New Innovator Awards (1DP2OD007363 and 1DP2OD008398), as well as NIH U19 A1063603, NIH R00 LM011384 and IADC P30 AG010133.

Source: Eric Schoch Indiana University Image Source: This NeuroscienceNews.com image is in the public domain. Original Research: Abstract for Mood, stress and longevity: convergence on ANK3 by S Rangaraju, D F Levey, K Nho, N Jain, K D Andrews, H Le-Niculescu, D R Salomon, A J Saykin, M Petrascheck & A B Niculescu in Molecular Psychiatry. Published online May 24 2016 doi:10.1038/mp.2016.65

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Indiana University. Genes Linked to the Effect of Stress and Mood on Longevity Identified. NeuroscienceNews. NeuroscienceNews, 24 May 2016. <http://neurosciencenews.com/mood-longevity-genetics-4285/>.

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Abstract

Mood, stress and longevity: convergence on ANK3

Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment-related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival effects in older worms. Thus, ANK3/unc-44 may represent an example of antagonistic pleiotropy, in which low-expression level in young animals are beneficial, but the age-associated increase becomes detrimental. Inactivating mutations in ANK3/unc-44 reverse this effect and cause detrimental effects in young animals (sensitivity to oxidative stress) and beneficial effect in old animals (increased survival). In humans, we studied if the most significant single nucleotide polymorphism (SNP) for depressive symptoms in ANK3 from our GWAS has a relationship to lifespan, and show a trend towards longer lifespan in individuals with the risk allele for depressive symptoms in men (odds ratio (OR) 1.41, P=0.031) but not in women (OR 1.08, P=0.33). We also examined whether ANK3, by itself or in a panel with other top CFG-prioritized genes, acts as a blood gene-expression biomarker for biological age, in two independent cohorts, one of live psychiatric patients (n=737), and one of suicide completers from the coroners office (n=45). We show significantly lower levels of ANK3 expression in chronologically younger individuals than in middle age individuals, with a diminution of that effect in suicide completers, who presumably have been exposed to more severe and acute negative mood and stress. Of note, ANK3 was previously reported to be overexpressed in fibroblasts from patients with HutchinsonGilford progeria syndrome, a form of accelerated aging. Taken together, these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and longevity/aging, that may be biomarkers as well as targets for preventive or therapeutic interventions. Drug repurposing bioinformatics analyses identified the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol as potential longevity promoting compounds, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and sirolimus/rapamycin. Intriguingly, some of our top candidate genes for mood and stress-modulated longevity were changed in expression in opposite direction in previous studies in the Alzheimer disease. Additionally, a whole series of others were changed in expression in opposite direction in our previous studies on suicide, suggesting the possibility of a life switch actively controlled by mood and stress.

Mood, stress and longevity: convergence on ANK3 by S Rangaraju, D F Levey, K Nho, N Jain, K D Andrews, H Le-Niculescu, D R Salomon, A J Saykin, M Petrascheck & A B Niculescu in Molecular Psychiatry. Published online May 24 2016 doi:10.1038/mp.2016.65

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AgingAlzheimer's diseaseANK3emotionGeneticsGoldilocks effectHutchinson-Gilford progeria syndromelongevitymitochondriamoodPsychologystresssuicide

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