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1.  Place and Cause of Death in Centenarians: A Population-Based Observational Study in England, 2001 to 2010 
PLoS Medicine  2014;11(6):e1001653.
Catherine J. Evans and colleagues studied how many and where centenarians in England die, their causes of death, and how these measures have changed from 2001 to 2010.
Please see later in the article for the Editors' Summary
Centenarians are a rapidly growing demographic group worldwide, yet their health and social care needs are seldom considered. This study aims to examine trends in place of death and associations for centenarians in England over 10 years to consider policy implications of extreme longevity.
Methods and Findings
This is a population-based observational study using death registration data linked with area-level indices of multiple deprivations for people aged ≥100 years who died 2001 to 2010 in England, compared with those dying at ages 80-99. We used linear regression to examine the time trends in number of deaths and place of death, and Poisson regression to evaluate factors associated with centenarians’ place of death. The cohort totalled 35,867 people with a median age at death of 101 years (range: 100–115 years). Centenarian deaths increased 56% (95% CI 53.8%–57.4%) in 10 years. Most died in a care home with (26.7%, 95% CI 26.3%–27.2%) or without nursing (34.5%, 95% CI 34.0%–35.0%) or in hospital (27.2%, 95% CI 26.7%–27.6%). The proportion of deaths in nursing homes decreased over 10 years (−0.36% annually, 95% CI −0.63% to −0.09%, p = 0.014), while hospital deaths changed little (0.25% annually, 95% CI −0.06% to 0.57%, p = 0.09). Dying with frailty was common with “old age” stated in 75.6% of death certifications. Centenarians were more likely to die of pneumonia (e.g., 17.7% [95% CI 17.3%–18.1%] versus 6.0% [5.9%–6.0%] for those aged 80–84 years) and old age/frailty (28.1% [27.6%–28.5%] versus 0.9% [0.9%–0.9%] for those aged 80–84 years) and less likely to die of cancer (4.4% [4.2%–4.6%] versus 24.5% [24.6%–25.4%] for those aged 80–84 years) and ischemic heart disease (8.6% [8.3%–8.9%] versus 19.0% [18.9%–19.0%] for those aged 80–84 years) than were younger elderly patients. More care home beds available per 1,000 population were associated with fewer deaths in hospital (PR 0.98, 95% CI 0.98–0.99, p<0.001).
Centenarians are more likely to have causes of death certified as pneumonia and frailty and less likely to have causes of death of cancer or ischemic heart disease, compared with younger elderly patients. To reduce reliance on hospital care at the end of life requires recognition of centenarians’ increased likelihood to “acute” decline, notably from pneumonia, and wider provision of anticipatory care to enable people to remain in their usual residence, and increasing care home bed capacity.
Please see later in the article for the Editors' Summary
Editors’ Summary
People who live to be more than 100 years old—centenarians—are congratulated and honored in many countries. In the UK, for example, the Queen sends a personal greeting to individuals on their 100th birthday. The number of UK residents who reach this notable milestone is increasing steadily, roughly doubling every 10 years. The latest Office of National Statistics (ONS) figures indicate that 13,350 centenarians were living in the UK in 2012 (20 centenarians per 100,000 people in the population) compared to only 7,740 in 2002. If current trends continue, by 2066 there may be more than half a million centenarians living in the UK. And similar increases in the numbers of centenarians are being seen in many other countries. The exact number of centenarians living worldwide is uncertain but is thought to be around 317,000 and is projected to rise to about 18 million by the end of this century.
Why Was This Study Done?
Traditional blessings often include the wish that the blessing’s recipient lives to be at least 100 years old. However, extreme longevity is associated with increasing frailty—declining physical function, increasing disability, and increasing vulnerability to a poor clinical outcome following, for example, an infection. Consequently, many centenarians require 24-hour per day care in a nursing home or a residential care home. Moreover, although elderly people, including centenarians, generally prefer to die in a home environment rather than a clinical environment, many centenarians end up dying in a hospital. To ensure that centenarians get their preferred end-of-life care, policy makers and clinicians need to know as much as possible about the health and social needs of this specific and unique group of elderly people. In this population-based observational study, the researchers examine trends in the place of death and factors associated with the place of death among centenarians in England over a 10-year period.
What Did the Researchers Do and Find?
The researchers extracted information about the place and cause of death of centenarians in England between 2001 and 2010 from the ONS death registration database, linked these data with area level information on deprivation and care-home bed capacity, and analyzed the data statistically. Over the 10-year study period, 35,867 centenarians (mainly women, average age 101 years) died in England. The annual number of centenarian deaths increased from 2,823 in 2001 to 4,393 in 2010. Overall, three-quarters of centenarian death certificates stated “old age” as the cause of death. About a quarter of centenarians died in the hospital, a quarter died in a nursing home, and a third died in a care home without nursing; only one in ten centenarians died at home. The proportion of deaths in a nursing home increased slightly over the study period but there was little change in the number of hospital deaths. Compared with younger age groups (80–84 year olds), centenarians were more likely to die from pneumonia and “old age” and less likely to die from cancer and heart disease. Among centenarians, dying in the hospital was more likely to be reported to be associated with pneumonia or heart disease than with dementia; death in the hospital was also associated with having four or more contributing causes of death and with living in a deprived area. Finally, living in an area with a higher care-home bed capacity was associated with a lower risk of dying in the hospital.
What Do These Findings Mean?
These findings suggest that many centenarians have outlived death from the chronic diseases that are the common causes of death among younger groups of elderly people and that dying in the hospital is often associated with pneumonia. Overall, these findings suggest that centenarians are a group of people living with a risk of death from increasing frailty that is exacerbated by acute lung infection. The accuracy of these findings is likely to be affected by the quality of UK death certification data. Although this is generally high, the strength of some of the reported associations may be affected, for example, by the tendency of clinicians to record the cause of death in the very elderly as “old age” to provide some comfort to surviving relatives. Importantly, however, these findings suggest that care-home capacity and the provision of anticipatory care should be increased in England (and possibly in other countries) to ensure that more of the growing number of centenarians can end their long lives outside hospital.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute on Aging provides information about healthy aging, including information on longevity (in English and Spanish)
The National End of Life Care Intelligence Network, England is a government organization that gathers data on care provided to adults approaching the end of life to improve service quality and productivity
The Worldwide Palliative Care Alliance promotes universal access to affordable palliative care through the support of regional and national palliative care organizations
The non-for-profit organization AgeUK provides information about all aspects of aging
Wikipedia has a page on centenarians (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The International Longevity Centre-UK is an independent, non-partisan think tank dedicated to addressing issues of longevity, ageing and population; its “Living Beyond 100” report examines the research base on centenarians and calls for policy to reflect the ongoing UK increase in extreme longevity
This study is part of GUIDE_Care, a project initiated by the Cicely Saunders Institute to investigate patterns in place of death and the factors that affect these patterns
PMCID: PMC4043499  PMID: 24892645
2.  Lipoprotein Particle Profiles Mark Familial and Sporadic Human Longevity 
PLoS Medicine  2006;3(12):e495.
Genetic and biochemical studies have indicated an important role for lipid metabolism in human longevity. Ashkenazi Jewish centenarians and their offspring have large low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles as compared with control individuals. This profile also coincided with a lower prevalence of disease. Here, we investigate whether this observation can be confirmed for familial longevity in an outbred European population and whether it can be extended to sporadic longevity in the general population.
Methods and Findings
NMR-measured lipoprotein profiles were analyzed in 165 families from the Leiden Longevity Study, consisting of 340 long-lived siblings (females >91 y, males >89 y), 511 of their offspring, and 243 partners of the offspring. Offspring had larger (21.3 versus 21.1 nm; p = 0.020) and fewer (1,470 versus 1,561 nmol/l; p = 0.011) LDL particles than their same-aged partners. This effect was even more prominent in the long-lived siblings (p < 10−3) and could be pinpointed to a reduction specifically in the concentration of small LDL particles. No differences were observed for HDL particle phenotypes. The mean LDL particle sizes in 259 90-y-old singletons from a population-based study were similar to those in the long-lived siblings and thus significantly larger than in partners of the offspring, suggesting that the relevance of this phenotype extends beyond familial longevity. A low concentration of small LDL particles was associated with better overall health among both long-lived siblings (p = 0.003) and 90-y-old singletons (p = 0.007).
Our study indicates that LDL particle profiles mark both familial and sporadic human longevity already in middle age.
Offspring of families from the Leiden Longevity Study had larger and fewer LDL particles than same-aged partners, suggesting that even in middle age LDL particle profiles are associated with longevity.
Editors' Summary
It is not clear why some people go on to live longer than others do. Some studies have shown that close relatives of long-lived people are themselves more likely to live for a long time; these findings suggest that there is probably a genetic basis for long life. However, the actual mechanisms involved have not yet been worked out. Some genes coding for proteins involved in fat metabolism, such as APOE, APOB, and CETP, have been associated with long life, suggesting a link between the way fat gets metabolized and the aging process. One study that supports this idea found that the children of 100-year-old people had larger lipoprotein particles (assemblies of proteins and fats that carry cholesterol and triglycerides in the blood) than similarly aged control individuals. However, studies such as this are very prone to “false positive” findings and therefore need to be backed up by confirmatory evidence. In addition, the previous study was performed in a very specific population (Ashkenazi Jewish people), and it is important to find out whether the findings are also true in other populations.
Why Was This Study Done?
The research group carrying out this study wanted to address several distinct questions to do with the genetics of aging. Firstly, they wanted to see if they could confirm previous findings associating large lipoprotein particles with longer life, but looking at people who were more representative of the general European population and not from a genetically isolated population. Secondly, they wanted to see whether this association applied to only long-lived people whose family members were also long-lived, or to long-lived people in general. Finally, they wanted to find out if the large lipoprotein particles were associated with better health.
What Did the Researchers Do and Find?
In the study, the researchers looked at long-lived people from across The Netherlands whose relatives were also long-lived. For this, they recruited 340 men aged over 89 and women aged over 91 into the study, all of whom had at least one similarly long-lived sister or brother. Their children (511 individuals), and the partners of their children (243 people), were also recruited into the study, with the partners acting as “controls.” The researchers also studied 259 people who had just turned 90 years old; these people were included to see whether particular characteristics of lipoproteins existed in long-lived people whose longevity did not run in families. All the participants gave blood samples, and the researchers then measured the size and amount of different lipoprotein particles in these samples. Two types of lipoprotein particles were looked at: low-density lipoprotein (LDL, often termed “bad cholesterol”) and high-density lipoprotein (HDL, sometimes called “good cholesterol”). The researchers found that the children from the long-lived people had larger and fewer LDL particles than their partners (the “control” individuals) just like their long-lived parents. Thus even though the children were not long-lived themselves, LDL particles marked the fact that they have a higher chance of becoming long-lived in the future. Similar changes in LDL particles were found for long-lived people whose relatives were not also long-lived. Interestingly, simply the level of cholesterol—the classical risk factor for cardiovascular disease—did not appear to play a role. Thus it seems that it is not the amount of cholesterol that is important in longevity but how it is packaged. Better health status was also associated with a lower proportion of small LDL particles in the blood, supporting these findings. No characteristics of the HDL particles seemed to be associated with longevity.
What Do These Findings Mean?
These findings confirm those from a previous study in Ashkenazi Jewish people that suggested that the size of LDL particles in the blood was associated with long life. The nature of this association is not clear; some studies indicated that small LDL particles increase the risk of cardiovascular disease but small LDL particles may also be harmless themselves and reflect the efficiency of other processes causally related to aging.
Additional Information.
Please access these Web sites via the online version of this summary at
Wikipedia chapter on senescence (biology of aging) (note that Wikipedia is a free Internet encyclopedia that anyone can edit)
US National Institute on Aging provides information on healthy aging, details of publicly funded research into aging, and other resources for the public
Help the Aged information on research into aging
PMCID: PMC1716190  PMID: 17194192
3.  Predictors of Exceptional Longevity: Effects of Early-Life Childhood Conditions, Midlife Environment and Parental Characteristics 
Living to 100 monograph  2014;2014:1-18.
Knowledge of strong predictors of mortality and longevity is very important for actuarial science and practice. Earlier studies found that parental characteristics as well as early-life conditions and midlife environment play a significant role in survival to advanced ages. However, little is known about the simultaneous effects of these three factors on longevity. This ongoing study attempts to fill this gap by comparing centenarians born in the United States in 1890–91 with peers born in the same years who died at age 65. The records for centenarians and controls were taken from computerized family histories, which were then linked to 1900 and 1930 U.S. censuses. As a result of this linkage procedure, 765 records of confirmed centenarians and 783 records of controls were obtained.
Analysis with multivariate logistic regression found that parental longevity and some midlife characteristics proved to be significant predictors of longevity while the role of childhood conditions was less important. More centenarians were born in the second half of the year compared to controls, suggesting early origins of longevity. We found the existence of both general and gender-specific predictors of human longevity. General predictors common for men and women are paternal and maternal longevity. Gender-specific predictors of male longevity are the farmer occupation at age 40, Northeastern region of birth in the United States and birth in the second half of year. A gender-specific predictor of female longevity is surprisingly the availability of radio in the household according to the 1930 U.S. census.
Given the importance of familial longevity as an independent predictor of survival to advanced ages, we conducted a comparative study of biological and nonbiological relatives of centenarians using a larger sample of 1,945 validated U.S. centenarians born in 1880–95. We found that male gender of centenarian has significant positive effect on survival of adult male relatives (brothers and fathers) but not female blood relatives. Life span of centenarian siblings-in-law is lower compared to life span of centenarian siblings and does not depend on centenarian gender. Wives of male centenarians (who share lifestyle and living conditions) have a significantly better survival compared to wives of centenarians' brothers. This finding demonstrates an important role of shared familial environment and lifestyle in human longevity.
The results of this study suggest that familial background, early-life conditions and midlife characteristics play an important role in longevity.
PMCID: PMC4318523  PMID: 25664346
4.  Buffering Mechanisms in Aging: A Systems Approach Toward Uncovering the Genetic Component of Aging 
PLoS Computational Biology  2007;3(8):e170.
An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the “oldest old” Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows disease-related genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidate-buffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.
Author Summary
Previous research showed that the frequency of deleterious genotype of some age-related disease decreases its prevalence as the population ages, as expected, since subjects with deleterious genotype are weeded out due to mortality. There exists, however, a set of age-related genes whose deleterious genotype indeed decreases up to ages 80–85, but subsequently increases monotonically, until by age 100 its prevalence is similar to that at age ∼60. Why is a known harmful genotype so prevalent among centenarians? Most likely because this genotype is protected by longevity genes. We corroborated this hypothesis by studying gene–gene interactions between age-related disease genotypes and longevity genotypes. Our findings suggest that individuals with the favorable longevity genotype can have just as many deleterious aging genotypes as the rest of the population because their longevity genotype protects them from the harmful effects of the other. We identify genes contributing to extreme lifespan as well as their counterpart, age-related disease genes. Our findings provide a proof of concept for the utility of high-throughput methods, and for elucidating mechanisms by which longevity genes buffer the effects of disease genes. Our approach gives hope for developing new medications that will protect against several age-related diseases.
PMCID: PMC1963511  PMID: 17784782
5.  Oxidative Stress and Longevity in Okinawa: An Investigation of Blood Lipid Peroxidation and Tocopherol in Okinawan Centenarians 
Background. The Free Radical Theory of Aging mechanistically links oxidative stress to aging. Okinawa has among the world's longest-lived populations but oxidative stress in this population has not been well characterized. Methods. We compared plasma lipid peroxide (LPO) and vitamin E—plasma and intracellular tocopherol levels (total α, β, and γ), in centenarians with younger controls. Results. Both LPO and vitamin E tocopherols were lower in centenarians, with the exception of intracellular β-tocopherol, which was significantly higher in centenarians versus younger controls. There were no significant differences between age groups for tocopherol: cholesterol and tocopherol: LPO ratios. Correlations were found between α-Tocopherol and LPO in septuagenarians but not in centenarians. Conclusions. The low plasma level of LPO in Okinawan centenarians, compared to younger controls, argues for protection against oxidative stress in the centenarian population and is consistent with the predictions of the Free Radical Theory of Aging. However, the present work does not strongly support a role for vitamin E in this phenomenon. The role of intracellular β-tocopherol deserves additional study. More research is needed on the contribution of oxidative stress and antioxidants to human longevity.
PMCID: PMC3068305  PMID: 21490698
6.  The application of genetics approaches to the study of exceptional longevity in humans: potential and limitations 
The average life-span of the population of industrialized countries has improved enormously over the last decades. Despite evidence pointing to the role of food intake in modulating life-span, exceptional longevity is still considered primarily an inheritable trait, as pointed out by the description of families with centenarian clusters and by the elevated relative probability of siblings of centenarians to become centenarians themselves. However, rather than being two separate concepts, the genetic origin of exceptional longevity and the more recently observed environment-driven increase in the average age of the population could possibly be explained by the same genetic variants and environmentally modulated mechanisms (caloric restriction, specific nutrients). In support of this hypothesis, polymorphisms selected for in the centenarian population as a consequence of demographic pressure have been found to modulate cellular signals controlled also by caloric restriction. Here, we give an overview of the recent findings in the field of the genetics of human exceptional longevity, of how some of the identified polymorphisms modulate signals also influenced by food intake and caloric restriction, of what in our view have been the limitations of the approaches used over the past years to study genetics (sib-pair-, candidate gene association-, and genome-wide association-studies), and briefly of the limitations and the potential of the new, high-throughput, next-generation sequencing techniques applied to exceptional longevity.
PMCID: PMC3407776  PMID: 22524405
Aging; Centenarians; Longevity
7.  Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans 
PLoS Medicine  2007;4(3):e76.
Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood.
Methods and Findings
The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 ± 1.0 y), overweight (body mass index, 27.8 ± 0.7 kg/m2) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, −135 ± 42 kcal/d, p = 0.002 and CREX, −117 ± 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% ± 5% in the CR group (p = 0.005) and 21% ± 4% in the CREX group (p < 0.004), with no change in the control group (2% ± 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (−0.56 ± 0.11 arbitrary units, p = 0.003) and CREX (−0.45 ± 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR.
The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults.
Anthony Civitarese and colleagues observed an increase in mitochondrial DNA in muscle and a decrease in whole body oxygen consumption in healthy adults who underwent caloric restriction.
Editors' Summary
Life expectancy (the average life span) greatly increased during the 20th century in most countries, largely due to improved hygiene, nutrition, and health care. One possible approach to further increase human life span is “caloric restriction.” A calorie-restricted diet provides all the nutrients necessary for a healthy life but minimizes the energy (calories) supplied in the diet. This type of diet increases the life span of mice and delays the onset of age-related chronic diseases such as heart disease and stroke. There are also hints that people who eat a calorie-restricted diet might live longer than those who overeat. People living in Okinawa, Japan, have a lower energy intake than the rest of the Japanese population and an extremely long life span. In addition, calorie-restricted diets beneficially affect several biomarkers of aging, including decreased insulin sensitivity (a precursor to diabetes). But how might caloric restriction slow aging? A major factor in the age-related decline of bodily functions is the accumulation of “oxidative damage” in the body's proteins, fats, and DNA. Oxidants—in particular, chemicals called “free radicals”—are produced when food is converted to energy by cellular structures called mitochondria. One theory for how caloric restriction slows aging is that it lowers free-radical production by inducing the formation of efficient mitochondria.
Why Was This Study Done?
Despite hints that caloric restriction might have similar effects in people as in rodents, there have been few well-controlled studies on the effect of good quality calorie-reduced diets in healthy people. It is also unknown whether an energy deficit produced by increasing physical activity while eating the same amount of food has the same effects as caloric restriction. Finally, it is unclear how caloric restriction alters mitochondrial function. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) organization is investigating the effect of caloric restriction interventions on physiology, body composition, and risk factors for age-related diseases. In this study, the researchers have tested the hypothesis that short-term caloric deficit (with or without exercise) increases the efficiency of mitochondria in human muscle.
What Did the Researchers Do and Find?
The researchers enrolled 36 healthy overweight but non-obese young people into their study. One-third of them received 100% of their energy requirements in their diet; the caloric restriction (CR) group had their calorie intake reduced by 25%; and the caloric restriction plus exercise (CREX) group had their calorie intake reduced by 12.5% and their energy expenditure increased by 12.5%. The researchers found that a 25% caloric deficit for six months, achieved by diet alone or by diet plus exercise, decreased 24-hour whole body energy expenditure (i.e., overall calories burned for body function), which suggests improved mitochondrial function. Their analysis of genes involved in mitochondria formation indicated that CR and CREX both increased the number of mitochondria in skeletal muscle. Both interventions also reduced the amount of DNA damage—a marker of oxidative stress—in the participants' muscles.
What Do These Findings Mean?
These results indicate that a short-term caloric deficit, whether achieved by diet or by diet plus exercise, induces the formation of “efficient mitochondria” in people just as in rodents. The induction of these efficient mitochondria in turn reduces oxidative damage in skeletal muscles. Consequently, this adaptive response to caloric restriction might have the potential to slow aging and increase longevity in humans as in other animals. However, this six-month study obviously provides no direct evidence for this, and, by analogy with studies in rodents, an increase in longevity might require lifelong caloric restriction. The results here suggest that even short-term caloric restriction can produce beneficial physiological changes, but more research is necessary before it becomes clear whether caloric restriction should be recommended to healthy individuals.
Additional Information.
Please access these Web sites via the online version of this summary at
The CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) Web site contains information on the study and how to participate
American Federation for Aging Research includes information on aging with pages on the biology of aging and on caloric restriction
The Okinawa Centenarian Study is a population-based study on long-lived elderly people in Okinawa, Japan
US Government information on nutrition
MedlinePlus encyclopedia pages on diet and calories
The Calorie Restriction Society, a nonprofit organization that provides information on life span and caloric restriction
Wikipedia pages on calorie restriction and on mitochondria (note: Wikipedia is an online encyclopedia that anyone can edit)
PMCID: PMC1808482  PMID: 17341128
8.  Genetics of healthy aging and longevity 
Human Genetics  2013;132(12):1323-1338.
Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may ‘buffer’ the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.
PMCID: PMC3898394  PMID: 23925498
9.  GNB3, eNOS, and Mitochondrial DNA Polymorphisms Correlate to Natural Longevity in a Xinjiang Uygur Population 
PLoS ONE  2013;8(12):e81806.
In centenarian populations, application of the positive biology approach (examination of positive phenotypes in aging) has revealed that mitochondrial DNA (mtDNA) mutation accumulation may be linked to human longevity; however, the role of guanine nucleotide-binding protein (G protein) abnormalities modulated by G-protein beta-3 (GNB3) and nitrate (NO2) production associated with endothelial nitric oxide synthase (eNOS), commonly appearing in age-related diseases, remains undetermined.
The association between the mtDNA 5178A/C, mtDNA 10398A/G, GNB3 C825T, and eNOS polymorphisms and longevity in a Uygur population (Xinjiang region, China) were investigated.
A total of 275 experimental subjects aged ≥100 or with 4 generations currently living were screened for inclusion in the centenarian (>100 years) and nonagenarian groups (90–100 years), and 112 65–70 year old control subjects were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to examine mtDNA 5178A/C, mtDNA 10398A/G, GNB3 C825T, and eNOS. Associations between polymorphic loci, genotypes, and longevity were analyzed.
165 included subjects (M∶F = 107∶58; mean age = 97±3 years; mean age 100–113 years) were assigned to the centenarian (M∶F = 46/19; n = 65) and nonagenarian groups (M∶F = 61/39; n = 100). Associations between mtDNA C5178A and A10398G polymorphisms with longevity in the centenarian group with mtDNA genotype frequencies 5178A and 10398G were 66.79% and 36.8%.
Applying the overwhelming longevity observed in Uygur populations, these findings demonstrate that mtDNA 5178A/C and 10398A/G, GNB3 C825T, and eNOS polymorphisms are useful as a genetic basis for longevity.
PMCID: PMC3869651  PMID: 24376503
10.  Meta-analysis of genetic variants associated with human exceptional longevity 
Aging (Albany NY)  2013;5(9):653-661.
Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non-centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta-analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population.
PMCID: PMC3808698  PMID: 24244950
centenarian; exceptional longevity; genetic association study; aging; gene; lifespan; meta-analysis
11.  Discovery of novel non-synonymous SNP variants in 988 candidate genes from 6 centenarians by target capture and next-generation sequencing 
Mechanisms of ageing and development  2013;134(10):10.1016/j.mad.2013.01.005.
Despite evidence of a substantial genetic component, the genetic factors that underlie longevity in humans remain to be identified. Previous genome-wide linkage and association studies have not found strong evidence for the contribution of common variants besides the APOE gene, suggesting the role of rare variants in human longevity. To discover rare variants that might contribute to longevity, we selected 988 candidate genes and performed a pilot study to identify novel non-synonymous variants in 6 Ashkenazi Jewish centenarians older than 105. Our candidate genes act in pathways implicated in aging and longevity, including neurodegeneration, cognitive function, lipid metabolism, DNA repair, and genome maintenance. By implementing custom-designed Agilent SureSelect target capture and next-generation sequencing, we discovered a total of 89 novel non-synonymous SNPs (nsSNPs) and validated 51 nsSNPs by iPLEX MassArray assays. Genotyping analysis of these novel SNPs in 410 Ashkenazi Jewish controls and 390 centenarians showed significant enrichment (5.3 fold, p=0.02) of the p.Y318C variant in PMS2 and significant depletion (7.5 fold, p=0.04) of the p.V465A variant in GABRR3 in centenarians compared to controls. Our study presents the potential of targeted next-generation sequencing for discovery of rare but functional genetic variation which may lead to exceptional longevity in humans.
PMCID: PMC3787996  PMID: 23376243
Centenarian; Human longevity; Functional variant; Candidate genes; Target capture and next-generation sequencing
12.  Are centenarians genetically predisposed to lower disease risk? 
Age  2011;34(5):1269-1283.
Our study purpose was to compare a disease-related polygenic profile that combined a total of 62 genetic variants among (i) people reaching exceptional longevity, i.e., centenarians (n = 54, 100–108 years, 48 women) and (ii) ethnically matched healthy controls (n = 87, 19–43 years, 47 women). We computed a ‘global’ genotype score (GS) for 62 genetic variants (mutations/polymorphisms) related to cardiometabolic diseases, cancer or exceptional longevity, and also specific GS for main disease categories (cardiometabolic risk and cancer risk, including 36 and 24 genetic variations, respectively) and for exceptional longevity (7 genetic variants). The ‘global’ GS was similar among groups (centenarians: 31.0 ± 0.6; controls 32.0 ± 0.5, P = 0.263). We observed that the GS for hypertension, cancer (global risk), and other types of cancer was lower in the centenarians group compared with the control group (all P < 0.05), yet the difference became non significant after adjusting for sex. We observed significant between-group differences in the frequency of GSTT1 and GSTM1 (presence/absence) genotypes after adjusting for multiple comparisons. The likelihood of having the GSTT1 low-risk (functional) allele was higher in centenarians (odds ratio [OR] 5.005; 95% confidence interval [CI], 1.810–13.839), whereas the likelihood of having the GSTMI low-risk (functional) allele was similar in both groups (OR 1.295; 95% CI, 0.868 –1.931). In conclusion, we found preliminary evidence that Spanish centenarians have a lower genetic predisposition for cancer risk. The wild-type (i.e., functional) genotype of GSTT1, which is associated with lower cancer risk, might be associated with exceptional longevity, yet further studies with larger sample sizes must confirm these findings.
PMCID: PMC3448993  PMID: 21894447
Centenarians; Genetics; Exceptional longevity; Ageing
13.  The Genetics of Extreme Longevity: Lessons from the New England Centenarian Study 
Frontiers in Genetics  2012;3:277.
The New England Centenarian Study (NECS) was founded in 1994 as a longitudinal study of centenarians to determine if centenarians could be a model of healthy human aging. Over time, the NECS along with other centenarian studies have demonstrated that the majority of centenarians markedly delay high mortality risk-associated diseases toward the ends of their lives, but many centenarians have a history of enduring more chronic age-related diseases for many years, women more so than men. However, the majority of centenarians seem to deal with these chronic diseases more effectively, not experiencing disability until well into their nineties. Unlike most centenarians who are less than 101 years old, people who live to the most extreme ages, e.g., 107+ years, are generally living proof of the compression of morbidity hypothesis. That is, they compress morbidity and disability to the very ends of their lives. Various studies have also demonstrated a strong familial component to extreme longevity and now evidence particularly from the NECS is revealing an increasingly important genetic component to survival to older and older ages beyond 100 years. It appears to us that this genetic component consists of many genetic modifiers each with modest effects, but as a group they can have a strong influence.
PMCID: PMC3510428  PMID: 23226160
centenarians; genetic of longevity; heritability of longevity; compression of morbidity; genetic variation
14.  Season of Birth and Exceptional Longevity: Comparative Study of American Centenarians, Their Siblings, and Spouses 
Journal of Aging Research  2011;2011:104616.
This study explores the effects of month of birth (a proxy for early-life environmental influences) on the chances of survival to age 100. Months of birth for 1,574 validated centenarians born in the United States in 1880–1895 were compared to the same information obtained for centenarians' 10,885 shorter-lived siblings and 1,083 spouses. Comparison was conducted using a within-family analysis by the method of conditional logistic regression, which allows researchers to control for unobserved shared childhood or adulthood environment and common genetic background. It was found that months of birth have significant long-lasting effect on survival to age 100: siblings born in September–November have higher odds to become centenarians compared to siblings born in March. A similar month-of-birth pattern was found for centenarian spouses. These results support the idea of early-life programming of human aging and longevity.
PMCID: PMC3236478  PMID: 22187646
15.  Serum Heat Shock Protein 70 Level as a Biomarker of Exceptional Longevity 
Mechanisms of ageing and development  2006;127(11):862-868.
Heat shock proteins are highly conserved proteins that, when produced intracellularly, protect stress exposed cells. In contrast, extracellular Hsp70 has been shown to have both protective and deleterious effects. In this study, we assessed heat shock protein 70 (Hsp70) for its potential role in human longevity. Because of the importance of HSP to disease processes, cellular protection, and inflammation, we hypothesized that: (1) Hsp70 levels in centenarians and centenarian offspring are different from controls and (2) alleles in genes associated with Hsp70 explain these differences. In this cross-sectional study, we assessed serum Hsp70 levels from participants enrolled in either the New England Centenarian Study (NECS) or the Longevity Genes Project (LGP): 87 centenarians (from LGP), 93 centenarian offspring (from NECS), and 126 controls (43 from NECS, 83 from LGP). We also examined genotypic and allelic frequencies of polymorphisms in HSP70-A1A and HSP70-A1B in 347 centenarians (266 from the NECS, 81 from the LGP), 260 NECS centenarian offspring, and 238 controls (NECS: 53 spousal controls and 106 septuagenarian offspring controls; LGP: 79 spousal controls). The adjusted mean serum Hsp70 levels (ng/mL) for the NECS centenarian offspring, LGP centenarians, LGP spousal controls, and NECS controls were 1.05, 1.13, 3.05, 6.93, respectively, suggesting that a low serum Hsp70 level is associated with longevity; however, no genetic associations were found with two SNPs within two hsp70 genes.
PMCID: PMC1781061  PMID: 17027907
ageing; centenarian; chaperokine; heat shock proteins; longevity
16.  Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians 
Aging (Albany NY)  2014;6(11):944-951.
Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population.
PMCID: PMC4276788  PMID: 25553725
insulin-like growth factor binding protein 3; longevity; single nucleotide polymorphism
17.  The influence of gender on inheritance of exceptional longevity 
Aging (Albany NY)  2015;7(6):412-418.
While the search for genetic contributors to exceptional longevity has yielded candidates, gender differences in inheritance have generally not been considered. The aim of this study was to investigate gender specific differences in the inheritance of exceptional longevity. Using a standardized questionnaire, we assessed the parental ages of death of Ashkenazi Jews with exceptional longevity and their spouses without exceptional longevity, who served as controls (n=1,114). Mothers of centenarian males and females had significantly longer lifespans compared to the mothers of non‐ centenarians, 79.0 ± 13.4 vs. 73.0 ± 16.3 years, p<0.01 and 75.7 ± 15.8 vs. 70.5 ± 18.0 years, p=0.02, respectively. There was also a trend toward longer lifespan among the fathers of centenarian men compared to the lifespan of fathers of non‐ centenarian men, 73.5 ± 17.0 vs. 69.5 ±15.0 years, p=0.07. The lifespan did not differ between the fathers of centenarian and non‐centenarian daughters. Logistic regression models revealed that the odds of being a centenarian for the female and male offspring increased by 21% and 31%, respectively, for every additional 10 years of life achieved by the mother (p<0.05). These findings support a gender‐specific inheritance pattern of human longevity and may help focus the search for longevity genes.
PMCID: PMC4505167  PMID: 26142631
centenarians; longevity; gender; inheritance
18.  Are ‘Endurance’ Alleles ‘Survival’ Alleles? Insights from the ACTN3 R577X Polymorphism 
PLoS ONE  2011;6(3):e17558.
Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching ≥100years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein α-actinin-3. We compared the ACTN3 R577X genotype/allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n = 64; 57 female; age range: 100–108 years), young healthy controls (n = 283, 67 females, 216 males; 21±2 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P = 0.019) and XX genotype (P = 0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (α-actinin-3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by α-actinin-3 deficiency and the ‘endurance’/oxidative muscle phenotype that is commonly associated with this condition.
PMCID: PMC3048287  PMID: 21407828
19.  Centenarians – a useful model for healthy aging? A 29-year follow-up of hospitalizations among 40 000 Danes born in 1905 
Aging cell  2009;8(3):270-276.
Centenarians surpass the current human life expectancy with about 20–25 years. However, whether centenarians represent healthy aging still remains an open question. Previous studies have been hampered by a number of methodological shortcomings such as a cross-sectional design and lack of an appropriate control group. In a longitudinal population-based cohort, it was examined whether the centenarian phenotype may be a useful model for healthy aging. The study was based on a complete follow up of 39 945 individuals alive in the Danish 1905 birth cohort on January 1, 1977 identified through the Danish Civil Registration System (DCRS). Data from the Danish Demographic Database and The Danish National Patient Register (in existence since 1977) were used. The 1905 cohort was followed up from 1977 through 2004 with respect to hospitalizations and number of hospital days. Survival status was available until December 2006. Danish centenarians from the 1905 cohort were hospitalized substantially less than their shorter-lived contemporaries at the same point in time during the years 1977 through 2004. For example, at age 71–74, the proportion of nonhospitalized centenarians was 80.5% compared with 68.4% among individuals who died in their early 80s. This trend was evident in both sexes. As a result of their lower hospitalization rates and length of stay in hospital compared with their contemporaries, who died at younger ages, Danish centenarians represent healthy agers. Centenarians constitute a useful study population in the search for fixed traits associated with exceptional longevity, such as genotype.
PMCID: PMC2774420  PMID: 19627266
centenarians; exceptional longevity; fixed traits; healthy aging; hospitalization
20.  Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing 
BMC Genomics  2012;13:353.
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity.
We employed massively parallel sequencing technology to identify miRNAs expressed in B-cells from Ashkenazi Jewish centenarians, i.e., those living to a hundred and a human model of exceptional longevity, and younger controls without a family history of longevity. With data from 26.7 million reads comprising 9.4 × 108 bp from 3 centenarian and 3 control individuals, we discovered a total of 276 known miRNAs and 8 unknown miRNAs ranging several orders of magnitude in expression levels, a typical characteristics of saturated miRNA-sequencing. A total of 22 miRNAs were found to be significantly upregulated, with only 2 miRNAs downregulated, in centenarians as compared to controls. Gene Ontology analysis of the predicted and validated targets of the 24 differentially expressed miRNAs indicated enrichment of functional pathways involved in cell metabolism, cell cycle, cell signaling, and cell differentiation. A cross sectional expression analysis of the differentially expressed miRNAs in B-cells from Ashkenazi Jewish individuals between the 50th and 100th years of age indicated that expression levels of miR-363* declined significantly with age. Centenarians, however, maintained the youthful expression level. This result suggests that miR-363* may be a candidate longevity-associated miRNA.
Our comprehensive miRNA data provide a resource for further studies to identify genetic pathways associated with aging and longevity in humans.
PMCID: PMC3563618  PMID: 22846614
MicroRNA; Centenarians; Aging; Life span; Massively parallel sequencing
21.  Personality Traits of Centenarians’ Offspring 
To determine whether the offspring of centenarians have personality characteristics that are distinct from the general population.
Nationwide U.S. sample.
Unrelated offspring of centenarians (n = 246, mean age 75) were compared with published norms.
Using the NEO-Five-Factor Inventory (NEO-FFI) questionnaire, measures of the personality traits neuroticism, extraversion, openness, agreeableness, and conscientiousness were obtained. T-scores and percentiles were calculated according to sex and used to interpret the results.
Male and female offspring of centenarians scored in the low range of published norms for neuroticism and in the high range for extraversion. The women also scored comparatively high in agreeableness. Otherwise, both sexes scored within normal range for conscientiousness and openness, and the men scored within normal range for agreeableness.
Specific personality traits may be important to the relative successful aging demonstrated by the offspring of centenarians. Similarities across four of the five domains between male and female offspring is noteworthy and may relate to their successful aging. Measures of personality are an important phenotype to include in studies that assess genetic and environmental influences of longevity and successful aging.
PMCID: PMC2895990  PMID: 19392961
personality; longevity; centenarian; extraversion; neuroticism; agreeableness
22.  Analysis of HLA-DRB1,DQA1,DQB1 haplotypes in Sardinian centenarians 
Experimental gerontology  2007;43(2):114-118.
Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1∗15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a role in the association to diseases. Hence, we have evaluated, by amplification refractory mutation system/polymerase chain reaction (ARMS-PCR) the HLADQA1 and HLA-DQB1 allele frequencies in 123 centenarians and 92 controls from Sardinia to assess whether the association to HLA-DRB1∗15 allele may be due to the other genes involved in the HLA-DR,DQ haplotypes. The frequencies of HLA-DQA1,DQB1 haplotypes were not significantly modified in centenarians. Nevertheless by evaluating the frequency of DRB1∗15 linked haplotypes, we observed a not significant increase in centenarians of HLA-DQA1∗01,DQB1∗05 and HLA-DQA1∗01,DQB1∗06 haplotypes. These data suggest that these haplotypes might have a role in determining life span expectancy and longevity.
PMCID: PMC2645697  PMID: 17714903
Centenarians; HLA-DQA1; HLA-DQB1; Immune response; Longevity; Sardinia
23.  Lipoprotein Genotype and Conserved Pathway for Exceptional Longevity in Humans 
PLoS Biology  2006;4(4):e113.
Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians ( n = 213), their offspring ( n = 216), and an age-matched Ashkenazi control group ( n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the −641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) ( p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the −641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable −641C homozygote ( p < 0.0001). Homozygosity for the APOC3 −641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans.
An allele of apolipoprotein C3 (which regulates lipoprotein metabolism) is more prevalent in centenarian humans than controls. This genotype is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity.
PMCID: PMC1413567  PMID: 16602826
24.  Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity 
Age  2012;35(3):993-1005.
Longevity phenotype in humans results from the influence of environmental and genetic factors. Few gene polymorphisms have been identified so far with a modest effect on lifespan leaving room for the search of other players in the longevity game. It has been recently demonstrated that targeted disruption of the mouse homolog of the human angiotensin II type 1 receptor (AT1R) gene (AGTR1) translates into marked prolongation of animal lifespan (Benigni et al., J Clin Invest 119(3):524–530, 2009). Based on the above study in mice, here we sought to search for AGTR1 variations associated to reduced AT1 receptor protein levels and to prolonged lifespan in humans. AGTR1 was sequenced in 173 Italian centenarians and 376 younger controls. A novel non-synonymous mutation was detected in a centenarian. Two polymorphisms in AGTR1 promoter, rs422858 and rs275653, in complete linkage disequilibrium, were significantly associated with the ability to attain extreme old age. We then replicated the study of rs275653 in a large independent cohort of Japanese origin (598 centenarians and semi-supercentenarians, 422 younger controls) and indeed confirmed its association with exceptional old age. In combined analyses, rs275653 was associated to extreme longevity either at recessive model (P = 0.007, odds ratio (OR) 3.57) or at genotype level (P = 0.015). Significance was maintained after correcting for confounding factors. Fluorescence activated cell sorting analysis revealed that subjects homozygous for the minor allele of rs275653 had less AT1R-positive peripheral blood polymorphonuclear cells. Moreover, rs275653 was associated to lower blood pressure in centenarians. These findings highlight the role of AGTR1 as a possible candidate among longevity-enabling genes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9408-8) contains supplementary material, which is available to authorized users.
PMCID: PMC3636412  PMID: 22569962
Angiotensin II type I receptor; Genetic polymorphism; Centenarians; Human longevity
25.  Positive attitude towards life and emotional expression as personality phenotypes for centenarians 
Aging (Albany NY)  2012;4(5):359-367.
Centenarians have been reported to share particular personality traits including low neuroticism and high extraversion and conscientiousness. Since these traits have moderate to high heritability and are associated with various health outcomes, personality appears linked to bio-genetic mechanisms which may contribute to exceptional longevity. Therefore, the present study sought to detect genetically-based personality phenotypes in a genetically homogeneous sample of centenarians through developing and examining psychometric properties of a brief measure of the personality of centenarians, the Personality Outlook Profile Scale (POPS). The results generated two personality characteristics/domains, Positive Attitude Towards Life (PATL: optimism, easygoing, laughter, and introversion/outgoing) and Emotional Expression (EE: expressing emotions openly and not bottling up emotions). These domains demonstrated acceptable concurrent validity with two established personality measures, the NEO-Five Factor Inventory and Life Orientation Test-Revised. Additionally, centenarians in both groups had lower neuroticism and higher conscientiousness than the US adult population. Findings suggest that the POPS is a psychometrically sound measure of personality in centenarians and capture personality aspects of extraversion, neuroticism, and conscientiousness, as well as dispositional optimism which may contribute to successful aging.
PMCID: PMC3384436  PMID: 22626632
personality; measurement; Five-Factor Model; centenarians; aging

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