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Exceptional Human Longevity

Published:December 10, 2018DOI:https://doi.org/10.1016/j.mayocp.2018.10.005

      Abstract

      Exceptional longevity represents an extreme phenotype. Current centenarians are survivors of a cohort who display delayed onset of age-related diseases and/or resistance to otherwise lethal illnesses occurring earlier in life. Characteristics of aging are heterogeneous, even among long-lived individuals. Associations between specific clinical or genetic biomarkers exist, but there is unlikely to be a single biomarker predictive of long life. Careful observations in the oldest old offer some empirical strategies that favor increased health span and life span, with implications for compression of disability, identification and implementation of lifestyle behaviors that promote independence, identification and measurement of more reliable markers associated with longevity, better guidance for appropriate health screenings, and promotion of anticipatory health discussions in the setting of more accurate prognostication. Comprehensive PubMed literature searches were performed, with an unbiased focus on mechanisms of longevity. Overall, the aggregate literature supports that the basis for exceptional longevity is multifactorial and involves disparate combinations of genes, environment, resiliency, and chance, all of which are influenced by culture and geography.

      Abbreviations and Acronyms:

      ADLs (activities of daily living), BMI (body mass index), GH (growth hormone)
      Article Highlights
      • The mechanisms of extreme long life appear to be multifactorial and can be accomplished by disparate combinations of genes, environment, resiliency, and chance that vary with culture and geography.
      • Characteristics of aging are heterogeneous, even among long-lived individuals.
      • Associations between specific clinical or genetic biomarkers exist, but there is unlikely to be a single biomarker predictive of long life.
      • Careful observations in the oldest old offer some empirical strategies that favor increased health span and life span, including eating in moderation, regular exercise, purposeful living, and strong social support systems.
      Although the definition of exceptional longevity must at some level be arbitrary, major criteria should likely include the concepts of chronological vs biological age, as well as preservation of function. For successful aging, 2 assumptions exist: (1) that biological age, however determined, is less than chronological age and (2) functional status is maintained or the decline in functional status is relatively slowed or delayed. These assumptions are not unreasonable given that individuals who are exceptionally long-lived would necessarily tend to meet both criteria, or at least would have had to meet these criteria during some period leading up to their extreme longevity. For this review, comprehensive PubMed literature (1980-2018) searches were performed, with an unbiased focus on mechanisms of longevity.
      Evidence to date suggests that exceptional longevity involves interacting mechanisms that may be genetic, environmental, cultural, or geographic in origin. This review will examine the heterogeneous nature of exceptional longevity and how studying the oldest old may substantiate the involvement of the aforementioned mechanisms on the pace of aging, elucidate homeostatic responses characteristic of resiliency, suggest interventions in the aging process, and inform measurements of successful aging.

      Centenarians

      In 1995, it was estimated that during the span of human history the likelihood of living from birth to age 100 rose from 1 in 20 million to 1 in 50 for females in low-mortality nations such as Japan and Sweden
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      ; subsequent analyses published in 2009 indicated that this probability increased to approximately 1 in 2.
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      About 1 in 5000 persons in the United States is a centenarian or older,
      • Meyer J.
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      and this prevalence is predicted to markedly increase in the United States and other developed nations. Human longevity exceeds 115 years, with reliably reported ages of 122 years for Jeanne Calment who died in France in 1996
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      The oldest human.
      and 116 years for Jiroemon Kimura who died in Japan in 2013.
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      Although human life expectancy and median length of life rose dramatically over the past century, maximum life span has remained largely unchanged (Figure 1).
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      Chapter 4: Mortality, 2010-based NPP reference volume.
      Although the debate is ongoing, the weight of evidence suggests that there is a limit to human longevity, and indeed, over the past 2 decades, the ages at death of the longest surviving individuals have not significantly risen.
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      Conversely, arguments have been made that this lack of increase does not rule out the possibility that maximum human life span in years may quite gradually increase in the future.
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      Figure thumbnail gr1
      Figure 1Survivorship according to mortality rates experienced or projected in persons born 1851-2031 in England and Wales. Although mean life span has increased, maximum life span has remained essentially unchanged. From the UK Office for National Statistics,
      • UK Office for National Statistics
      Chapter 4: Mortality, 2010-based NPP reference volume.
      with permission granted by the United Kingdom Licensing Framework, Open Government License.
      In centenarians, the age at onset of common age-associated diseases, with the exception of cognitive impairment, is variable, with one or more diagnoses being made in 24% of males and 43% of females before 80 years of age. Approximately 43% of both male and female centenarians reach the age of 80 years before experiencing age-associated illness. Remarkably, there is an absence of any disease diagnosis in some 15% and 30% of female and male centenarians, respectively, at the age of 100 years. These results suggest that the onset of age-related conditions, regardless of sex differences, is heterogeneous and that their earlier manifestation (before 80) may still allow exceptional longevity.
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      Morbidity profiles of centenarians: survivors, delayers, and escapers.
      As many as 25% of centenarians are cognitively intact, and among those who reach 100 years of age and are not cognitively intact, the vast majority have delayed clinical onset of impairment until the average age of 92 years.
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      Dementia-free centenarians.
      Neurodegenerative disease and dementia do not occur in significant subsets of centenarians, and even in centenarians who exhibit neuropathologic markers of Alzheimer disease, criteria for dementia may be absent.
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      Dementia-free centenarians.
      Cancer is diagnosed at a substantially later age in centenarians.
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      Cancer in the oldest old.
      Supercentenarians (>110 years of age) may have development of vascular disease relatively late in life or not at all, and many are functionally independent or require minimal assistance.
      • Robine J.M.
      • Allard M.
      The oldest human.
      • Gondo Y.
      • Hirose N.
      • Yasumoto S.
      • Arai Y.
      • Saito Y.
      Age verification of the longest lived man in the world.
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      Characteristics of 32 supercentenarians.

      Geographic Clustering of Exceptionally Long-Lived Individuals

      Human subpopulations that display exceptionally long life spans illustrate the profound effects of environmental prolongevity factors. Long-lived Okinawans subscribe to the nutritional behavior of “hara haci bu” or “eat until you are only 80% full.” Their “rainbow diet” is based on diverse fruits and vegetables, with soy providing the bulk of protein intake.
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      Caloric restriction and human longevity: what can we learn from the Okinawans?.
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      • Suzuki M.
      The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load.
      Their daily caloric intake is substantially reduced compared with other diets, accounting for their low body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) (∼20 kg/m2) and suggesting that caloric restriction may contribute to their longevity. The association of lean body mass with exceptional longevity is also corroborated by studies in US centenarians born in the 1880s.
      • Gavrilova N.S.
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      Search for mechanisms of exceptional human longevity.
      Levels of dehydroepiandrosterone, the endogenous hormone secreted by the adrenal gland and a surrogate marker of life span extension, decline more slowly in Okinawans and mimic the trend seen in animal experiments of controlled caloric restriction.
      • Suzuki M.
      • Wilcox B.J.
      • Wilcox C.D.
      Implications from and for food cultures for cardiovascular disease: longevity.
      Compared with men elsewhere, men in Ovodda, Sardinia, tend to live longer.
      • Franceschi C.
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      • Valensin S.
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      Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE).
      Sardinians who emigrated in early adulthood or middle age are still capable of extreme longevity; their longevity may reflect their lineage from a select number of original settlers and that they remained isolated and interbred.
      • Passarino G.
      • Underhill P.A.
      • Cavalli-Sforza L.L.
      • et al.
      Y chromosome binary markers to study the high prevalence of males in Sardinian centenarians and the genetic structure of the Sardinian population.
      The basis for this male exceptional longevity may be related to as yet incompletely defined genetic traits.
      • Koenig R.
      Sardinia's mysterious male Methuselahs.
      Although Jiroemon Kimura had long-lived (nonagenarian) siblings, suggesting a possible genetic component to his longevity, he attributed his long life to several health practices including small apportioned meals.

      Kimura J. Japan’s century club swells to more than 40,000. 2009. Available at: https://www.webcitation.org/5rWEU7TEb?url=http://abcnews.go.com/International/wireStory?id=8544037. Accessed January 30, 2018.

      Seventh Day Adventists, largely residing in Loma Linda, California, outlive their fellow citizens by 5 to 10 years.
      • Fraser G.E.
      • Shavlik D.J.
      Ten years of life: is it a matter of choice?.
      • Lee J.W.
      • Morton K.R.
      • Walters J.
      • et al.
      Cohort profile: the Biopsychosocial Religion and Health Study (BRHS).
      Their religious faith requires abstinence from alcohol and tobacco, and recommends a vegetarian diet that is followed by many. Spirituality informs their daily living; indeed, life span is increased in regular churchgoers, whatever their faith.
      • Hall D.E.
      Religious attendance: more cost-effective than Lipitor?.
      • McCullough M.E.
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      • Koenig H.G.
      • Thoresen C.
      Religious involvement and mortality: a meta-analytic review.
      • Musick M.A.
      • House J.S.
      • Williams D.R.
      Attendance at religious services and mortality in a national sample.
      Seventh Day Adventists exhibit significantly lower levels of measured stress hormones.
      • Fraser G.E.
      Diet, Life Expectancy, and Chronic Disease: Studies of Seventh-day Adventists and Other Vegetarians.
      Other geographic clustering of long-lived individuals occurs in Costa Rica (Nicoya Peninsula), in Ikaria, Greece, and perhaps elsewhere.

      Azofeifa J, Ruiz-Narváez EA, Leal A, Gerlovin H, Rosero-Bixby L. Amerindian ancestry and extended longevity in Nicoya, Costa Rica [published online ahead of print September 8, 2017]. Am J Hum Biol. https://doi.org/10.1002/ajhb.23055.

      • Stefanadis C.I.
      Unveiling the secrets of longevity: the Ikaria study.
      There are several generalizations that can be made on the basis of common behavioral and environmental influences that may contribute to longevity in these areas (Table 1). These factors include eating in moderation and mostly plant-based diets, exercise that is incorporated into daily routines, purposeful living, maintaining social support systems, and other nutritional or behavioral factors that may underpin or reinforce healthy living.
      Table 1Longevity Factors Associated With Geographic Clustering of Long-Lived Populations
      Eating in moderation (small- or moderate-portioned “regular” meals), mostly plant-based diets, with lighter meals at the end of the day
      Purposeful living (eg, life philosophy, volunteerism, “hard work” or “work ethic”)
      Social support systems: interactions with family/friends, laughter/humor
      Exercise, especially walking, gardening
      Other nutritional factors: goat's milk, red wine, herbal teas
      Spirituality
      Maintenance of a healthy body mass index
      Other possible factors: sunshine, adequate hydration, naps

      Trends in Longevity

      Insights into trends and consequences of longer life can be gained through an understanding of human survivorship, demographics of longevity, and models of predicted morbidity as populations become long-lived. Japan remains one of the best examples of exceptional trends in increased longevity. However, regardless of location, concerns exist that enhanced longevity will be accompanied by more years of disability rather than more years of healthy life.
      Safeguarding against premature death, as opposed to variations in primary aging processes, underlies the survival benefit reflected by median life span and life expectancy (Figure 1). Reduction in the high rate of infant deaths (due to improved sanitation, nutrition, and immunization) largely accounts for protection from premature death by environmental hazards and infectious diseases seen early in the twentieth century.

      Masoro EJ. Aging: current concepts. In: Masoro EJ, ed. Handbook of Physiology. Section 11. New York, NY: Oxford University Press; 1995:3-21.

      Demographics of Longevity

      Japan, followed by Germany, Italy, Greece, Finland, and Sweden, had the world's oldest populations in 2015, with a longevity shift toward Asian populations expected by 2050, including Japan, South Korea, Hong Kong, and Taiwan.
      • He W.
      • Goodkind D.
      • Kowal P.
      An Aging World: 2015.
      In 2015, countries with the longest life expectancy at age 65 were Japan, Macau, Singapore, Australia, and Switzerland, with an additional 25.2 and 20.0 years of life expected for Japanese females and males, respectively.
      • He W.
      • Goodkind D.
      • Kowal P.
      An Aging World: 2015.
      In fact, in 2002, Japanese female life expectancy rose at a consistent rate of about 3 months per year for the preceding 160 years.
      • Oeppen J.
      • Vaupel J.W.
      Broken limits to life expectancy.
      In countries with the highest life expectancy, healthy life years vary between 25% and 75% of the predicted life expectancy at age 65 years.
      • He W.
      • Goodkind D.
      • Kowal P.
      An Aging World: 2015.
      Norway, Sweden, and Iceland have the greatest number of expected healthy years at age 65.
      • He W.
      • Goodkind D.
      • Kowal P.
      An Aging World: 2015.

      Compression of Morbidity

      There are several models of predicted morbidity proposed on the basis of extended longevity (Figure 2).
      • Fries J.F.
      Measuring and monitoring success in compressing morbidity.
      In one model of life extension, the age at initiation of morbidity remains constant and life years gained are accompanied by increased morbidity. In a second model, both the initiation of morbidity and the life years accrued are shifted to the right, with no gain or loss of morbidity. In a third model, initiation of morbidity is delayed and accompanied by added years accrued, resulting in the compression of morbidity.
      Figure thumbnail gr2
      Figure 2Possible scenarios for future morbidity and longevity. From Ann Intern Med, Fries JF, Measuring and monitoring success in compressing morbidity, Volume No. 139, Issue No. 5 (Part 2), Pages 455-459.
      • Fries J.F.
      Measuring and monitoring success in compressing morbidity.
      Copyright © 2003 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.
      Fries' “compression of morbidity” hypothesis puts forth the possibility that chronic morbidity begins at a later age and that the delay of onset would exceed the increase in life expectancy.
      • Fries J.F.
      Aging, natural death, and the compression of morbidity.
      In essence, for these longer-living individuals, the duration of chronic diseases and associated disability is diminished, with the attendant reduction in cumulative morbidity.
      Evidence that a reduction in disability trends of about 2% per year, accompanied by a 1% per year decline in mortality during the same period of time, supports this hypothesis.
      • Fries J.F.
      Frailty, heart disease, and stroke: the Compression of Morbidity paradigm.
      However, because the cohort of individuals 85 years or older comprises the most rapidly increasing sector of the American population, it is possible that compression of morbidity may not apply to individuals surviving to very old age. Delays in morbidity from age-onset diseases occur in many surviving to very old age; for others who survive to extreme old age, delay in disabilities alone is the essential requirement.
      • Terry D.F.
      • Sebastiani P.
      • Andersen S.L.
      • Perls T.T.
      Disentangling the roles of disability and morbidity in survival to exceptional old age.
      With some exceptions, estimated rates for the need for help in activities of daily living (ADLs) for aged individuals decreased during the 1980s and 1990s.
      • Schoeni R.F.
      • Freedman V.A.
      • Wallace R.B.
      Persistent, consistent, widespread, and robust? another look at recent trends in old-age disability.
      • Waidmann T.A.
      • Liu K.
      Disability trends among elderly persons and implications for the future.
      • Cutler D.M.
      Declining disability among the elderly.
      • Freedman V.A.
      • Agree E.M.
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      • Cornman J.C.
      Trends in the use of assistive technology and personal care for late-life disability, 1992-2001.
      • Schoeni R.F.
      • Freedman V.A.
      • Martin L.G.
      Why is late-life disability declining?.
      Some studies that covered the early years of the 21st century suggest a continued decline in rates of assistance needed by the elderly for ADLs, but others suggested a possible leveling off of these rates.
      • Cai L.
      • Lubitz J.
      Was there compression of disability for older Americans from 1992 to 2003?.
      • Fuller-Thomson E.
      • Yu B.
      • Nuru-Jeter A.
      • Guralnik J.M.
      • Minkler M.
      Basic ADL disability and functional limitation rates among older Americans from 2000-2005: the end of the decline?.
      • Martin L.G.
      • Schoeni R.F.
      • Andreski P.M.
      Trends in health of older adults in the United States: past, present, future.
      Data gathered from noninstitutionalized working-age adults and elderly individuals from 1984 to 2010 found that impairments in mobility and mental health decreased in the latter group.
      • Kaye H.S.
      Disability rates for working-age adults and for the elderly have stabilized, but trends for each mean different results for costs.
      As supercentenarians attain the current limit of human longevity, a later age at onset is increasingly seen for physical and cognitive impairment, age-related diseases, and overall age-dependent morbidity.
      • Andersen S.L.
      • Sebastiani P.
      • Dworkis D.A.
      • Feldman L.
      • Perls T.T.
      Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span.

      Why Are Some Individuals Long-Lived?

      Insights into possible mechanisms of human longevity point to genetic and environmental influences, sex differences, and resiliency. Twin studies have been important in differentiating genetic from environmental contributions to long life, and several theories have been put forward to explain increased longevity for women compared with men, including the role of reproduction and child-rearing. Resiliency, the capacity to adequately respond to stressors or resist typical age-related physiologic system-based changes, has also been implicated in conferring protection against insults that shorten life and health span.

      Genetic and Environmental Influences

      The genetic basis of longevity is supported by several lines of evidence: maximum life span is highly conserved in specific species; the age reached by monozygotic twins is remarkably similar, as compared with ages attained by dizygotic twins or by nontwin siblings; exceptional longevity is often observed within families; and premature aging syndromes, such as seen in syndromes of faulty DNA repair, among others, are genetically based. Centenarians' offspring have an increased likelihood of surviving to 100 years and exhibit a diminished prevalence of age-associated diseases.
      • Terry D.F.
      • Wilcox M.A.
      • McCormick M.A.
      • et al.
      Lower all-cause, cardiovascular, and cancer mortality in centenarians' offspring.
      Considering the ancestry of Jeanne Calment, a remarkable group of long-lived relatives existed in her family's preceding 5 generations, especially in her father's lineage, suggesting a largely genetic origin for her extreme longevity from paternal inheritance.
      • Robine J.M.
      • Allard M.
      The oldest human.
      Polymorphisms involving the APOE gene, the latter required in catabolizing triglyceride-rich lipoprotein constituents, may influence life span.
      • Eggertsen G.
      • Tegelman R.
      • Ericsson S.
      • Angelin B.
      • Berglund L.
      Apolipoprotein E polymorphism in a healthy Swedish population: variation of allele frequency with age and relation to serum lipid concentrations.
      Additionally, the apolipoprotein E ε4 allele occurs more frequently in middle-aged individuals compared with centenarians.
      • Louhija J.
      • Miettinen H.E.
      • Kontula K.
      • Tikkanen M.J.
      • Miettinen T.A.
      • Tilvis R.S.
      Aging and genetic variation of plasma apolipoproteins: relative loss of the apolipoprotein E4 phenotype in centenarians.
      Polymorphisms in other genes and their associated pathways implicated as imparting prolongevity effects include insulin/insulin-like growth factor 1, cholesteryl ester transfer protein, anti-inflammatory cytokines such as interleukin 10, RNA editing genes and stress response genes such as the heat shock protein 70 genes.
      • Bonafè M.
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      Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control.
      • Lio D.
      • Scola L.
      • Crivello A.
      • et al.
      Gender-specific association between -1082 IL-10 promoter polymorphism and longevity.
      • Singh R.
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      • Bross P.
      • et al.
      Heat-shock protein 70 genes and human longevity: a view from Denmark.
      • Barzilai N.
      • Atzmon G.
      • Schechter C.
      • et al.
      Unique lipoprotein phenotype and genotype associated with exceptional longevity.
      • Sebastiani P.
      • Montano M.
      • Puca A.
      • et al.
      RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans.
      Genome-wide association studies continue to identify new genetic variants for longevity.
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      • Kuo C.L.
      • Sicinski K.
      • et al.
      Human longevity: 25 genetic loci associated in 389,166 UK biobank participants.
      • Sebastiani P.
      • Gurinovich A.
      • Bae H.
      • et al.
      Four genome-wide association studies identify new extreme longevity variants.
      • Murabito J.M.
      • Yuan R.
      • Lunetta K.L.
      The search for longevity and healthy aging genes: insights from epidemiological studies and samples of long-lived individuals.
      Longevity-associated genes are postulated to be more conserved among long-lived species, to promote life span, and to be functionally enhanced in longer-lived species based on conservation of DNA or protein sequence information. Genes for breast cancer 1, early onset, and growth hormone (GH) receptor strongly associate with maximum life span across mammalian species.
      • Lindborg C.M.
      • Propert K.J.
      • Pignolo R.J.
      Conservation of pro-longevity genes among mammals.
      • Semeiks J.
      • Grishin N.V.
      A method to find longevity-selected positions in the mammalian proteome.
      The breast cancer 1, early onset, gene occurs with different genotype frequencies in centenarian populations compared with controls.
      • Vijg J.
      • Perls T.
      • Franceschi C.
      • van Orsouw N.J.
      BRCA1 gene sequence variation in centenarians.
      A GH receptor gene exon 3 deletion alters GH sensitivity, and the prevalence of homozygosity for the exon 3 deletion increases with age in long-lived individuals.
      • Ben-Avraham D.
      • Govindaraju D.R.
      • Budagov T.
      • et al.
      The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.
      In fact, exon 3 homozygosity adds approximately 10 years to life span and exhibits sexual dimorphism by positively affecting male longevity.
      • Ben-Avraham D.
      • Govindaraju D.R.
      • Budagov T.
      • et al.
      The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.
      Polymorphisms in genes protective against oxidative stress such as superoxide dismutase have not been found to be associated with long life. The GenAge database provides a comprehensive catalog of genes that may associate with human longevity.
      Gene Database (GenAge).
      Despite substantive evidence that genetic influences can positively affect longevity, environmental factors exert even greater effects. Indeed, as indicated by twin studies, no more than approximately 25% of the variance in adult human life span can be traced back to genetic differences.
      • Christensen K.
      • Johnson T.E.
      • Vaupel J.W.
      The quest for genetic determinants of human longevity: challenges and insights.
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      • McGue M.
      • Holm N.V.
      • Sørensen T.I.
      • Harvald B.
      • Vaupel J.W.
      The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870-1900.
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      • McGue M.
      • Iachine I.A.
      • et al.
      Untangling genetic influences on smoking, body mass index and longevity: a multivariate study of 2464 Danish twins followed for 28 years.
      This finding strongly suggests that behavior, environment, and health practices can profoundly affect the potential for long life.

      Sex Differences

      Universally, women live longer than men.
      • Austad S.N.
      • Bartke A.
      Sex differences in longevity and in responses to anti-aging interventions: a mini-review.
      • Austad S.N.
      • Fischer K.E.
      Sex differences in lifespan.
      Female babies also have better survival. In the United States, beginning at about age 55 years, the difference between the number of females and males roughly doubles by age 75 years and then doubles again by age 85 years and over.
      • He W.
      • Goodkind D.
      • Kowal P.
      An Aging World: 2015.
      Evolutionary pressure to extend human life span may also be closely linked to increasing the number of childbearing years for women.
      • Perls T.T.
      • Alpert L.
      • Fretts R.C.
      Middle-aged mothers live longer.
      Middle-aged mothers appear to live longer, and older maternal age at birth of the last child is associated with women's longevity.
      • Smith K.R.
      • Mineau G.P.
      • Bean L.L.
      Fertility and post-reproductive longevity.
      • Müller H.G.
      • Chiou J.M.
      • Carey J.R.
      • Wang J.L.
      Fertility and life span: late children enhance female longevity.
      • Sun F.
      • Sebastiani P.
      • Schupf N.
      • et al.
      Extended maternal age at birth of last child and women's longevity in the Long Life Family Study.
      There are conflicting results regarding the relationship between fecundity and longevity.
      • Lahdenperä M.
      • Lummaa V.
      • Helle S.
      • Tremblay M.
      • Russell A.F.
      Fitness benefits of prolonged post-reproductive lifespan in women.
      • Lockhart P.A.
      • Martin P.
      • Johnson M.A.
      • Shirtcliff E.
      • Poon L.W.
      The relationship of fertility, lifestyle, and longevity among women.
      • Tabatabaie V.
      • Atzmon G.
      • Rajpathak S.N.
      • Freeman R.
      • Barzilai N.
      • Crandall J.
      Exceptional longevity is associated with decreased reproduction.
      The duration of a female's postreproductive life span may influence the reproductive success of her offspring and her grandchildren's survival; this “grandmother hypothesis” may more likely involve maternal grandmothers.
      • Lahdenperä M.
      • Lummaa V.
      • Helle S.
      • Tremblay M.
      • Russell A.F.
      Fitness benefits of prolonged post-reproductive lifespan in women.
      • Jamison C.S.
      • Cornell L.L.
      • Jamison P.L.
      • Nakazato H.
      Are all grandmothers equal? a review and a preliminary test of the “grandmother hypothesis” in Tokugawa Japan.
      Length of postreproductive life in women may be related to their predominant role as caregivers, given that the caregiver role, at least in nonhuman primates, appears to be associated with greater longevity regardless of sex.
      • Allman J.
      • Rosin A.
      • Kumar R.
      • Hasenstaub A.
      Parenting and survival in anthropoid primates: caretakers live longer.
      The likelihood of living to be 100 years appears to be greater for offspring of younger vs older mothers, whereas paternal age does not exert a significant effect on longevity.
      • Gavrilov L.A.
      • Gavrilova N.S.
      Biodemography of exceptional longevity: early-life and mid-life predictors of human longevity.
      Sex differences are also seen in terms of longevity determinants, in which occupation history as well as relatedness to male centenarians are important factors for men and environmental conditions in the home or marriage to male centenarians (who share the same living conditions) are important to women.
      • Gavrilov L.A.
      • Gavrilova N.S.
      Biodemography of exceptional longevity: early-life and mid-life predictors of human longevity.
      • Gavrilov L.A.
      • Gavrilova N.S.
      Predictors of exceptional longevity: effects of early-life and midlife conditions, and familial longevity.
      To the extent that women tend to be shorter than men, a possible explanation for both greater longevity and lower height is diminished GH secretion.
      • Bartke A.
      Growth hormone and aging: a challenging controversy.
      • Bartke A.
      • Sun L.Y.
      • Longo V.
      Somatotropic signaling: trade-offs between growth, reproductive development, and longevity.
      • van der Spoel E.
      • Jansen S.W.
      • Akintola A.A.
      • et al.
      Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity.
      Despite the greater longevity of women, functional status is better in older men compared with older women.
      • Austad S.N.
      • Bartke A.
      Sex differences in longevity and in responses to anti-aging interventions: a mini-review.
      • Nakamura E.
      • Miyao K.
      Sex differences in human biological aging.

      Resiliency

      There is growing evidence to suggest that resiliency, or the ability to adequately respond to or resist various stressors, plays a key role in conferring successful aging.
      • Hadley E.C.
      • Kuchel G.A.
      • Newman A.B.
      • et al.
      Report: NIA Workshop on Measures of Physiologic Resiliencies in Human Aging.
      Although the mechanism(s) are poorly defined and may be tissue- or system-specific, examples of resiliency across multiple domains indicate that it contributes to health benefits in later life. Despite the paucity of human studies that address interventions that promote resiliency, animal investigations suggest that exercise (compared with calorie restriction) promotes resilience more effectively against diverse types of stress.
      • Huffman D.M.
      • Schafer M.J.
      • LeBrasseur N.K.
      Energetic interventions for healthspan and resiliency with aging.
      Resistance to stressors and disease that contributes to healthy aging is often described in the context of psychological resiliency, such as reduction of depression.
      • Jeste D.V.
      • Savla G.N.
      • Thompson W.K.
      • et al.
      Association between older age and more successful aging: critical role of resilience and depression.
      • Puterman E.
      • Epel E.S.
      • Lin J.
      • et al.
      Multisystem resiliency moderates the major depression-telomere length association: findings from the Heart and Soul Study.
      In fact, much work has been initiated describing the framework to study the effects of psychological and social factors on resistance to behavioral stressors that are common with aging.
      • Luthar S.S.
      • Cicchetti D.
      • Becker B.
      The construct of resilience: a critical evaluation and guidelines for future work.
      • Wagnild G.M.
      • Collins J.A.
      Assessing resilience.
      However, this aspect is different from physical and physiologic stressors and the homeostatic responses driven by resistance mechanisms against aging-related, system-specific declines and against multisystem insults, including loss of muscle strength,
      • Rantanen T.
      • Masaki K.
      • He Q.
      • Ross G.W.
      • Willcox B.J.
      • White L.
      Midlife muscle strength and human longevity up to age 100 years: a 44-year prospective study among a decedent cohort.
      impaired sleep quality and susceptibility to sleep disorders,
      • Parrino L.
      • Vaudano A.E.
      The resilient brain and the guardians of sleep: new perspectives on old assumptions.
      frailty,
      • Whitson H.E.
      • Duan-Porter W.
      • Schmader K.E.
      • Morey M.C.
      • Cohen H.J.
      • Colón-Emeric C.S.
      Physical resilience in older adults: systematic review and development of an emerging construct.
      skeletal aging,
      • Cauley J.A.
      • Lui L.Y.
      • Barnes D.
      • et al.
      Successful skeletal aging: a marker of low fracture risk and longevity; the Study of Osteoporotic Fractures (SOF).
      dementia (including Alzheimer disease),
      • Boyle P.A.
      • Yu L.
      • Wilson R.S.
      • Schneider J.A.
      • Bennett D.A.
      Relation of neuropathology with cognitive decline among older persons without dementia.
      • Knopman D.S.
      • Parisi J.E.
      • Salviati A.
      • et al.
      Neuropathology of cognitively normal elderly.
      • Latimer C.S.
      • Keene C.D.
      • Flanagan M.E.
      • et al.
      Resistance to Alzheimer disease neuropathologic changes and apparent cognitive resilience in the Nun and Honolulu-Asia Aging studies.
      • Mufson E.J.
      • Malek-Ahmadi M.
      • Perez S.E.
      • Chen K.
      Braak staging, plaque pathology, and APOE status in elderly persons without cognitive impairment.
      • Riley K.P.
      • Snowdon D.A.
      • Markesbery W.R.
      Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study.
      • SantaCruz K.S.
      • Sonnen J.A.
      • Pezhouh M.K.
      • Desrosiers M.F.
      • Nelson P.T.
      • Tyas S.L.
      Alzheimer disease pathology in subjects without dementia in 2 studies of aging: the Nun Study and the Adult Changes in Thought Study.
      • Schneider J.A.
      • Aggarwal N.T.
      • Barnes L.
      • Boyle P.
      • Bennett D.A.
      The neuropathology of older persons with and without dementia from community versus clinic cohorts.
      • Snowdon D.A.
      Healthy aging and dementia: findings from the Nun Study.
      • Sonnen J.A.
      • Santa Cruz K.
      • Hemmy L.S.
      • et al.
      Ecology of the aging human brain.
      and multimorbidity.
      • Wister A.V.
      • Coatta K.L.
      • Schuurman N.
      • Lear S.A.
      • Rosin M.
      • MacKey D.
      A lifecourse model of multimorbidity resilience: theoretical and research developments.
      There are likely direct relationships among resiliency against physical and physiologic stressors, homeostatic resistance mechanisms against aging-related, system-specific dysfunction, and longevity.
      • Cauley J.A.
      • Lui L.Y.
      • Barnes D.
      • et al.
      Successful skeletal aging: a marker of low fracture risk and longevity; the Study of Osteoporotic Fractures (SOF).
      • Ash A.S.
      • Kroll-Desrosiers A.R.
      • Hoaglin D.C.
      • Christensen K.
      • Fang H.
      • Perls T.T.
      Are members of long-lived families healthier than their equally long-lived peers? evidence from the Long Life Family Study.
      Resiliency is a plausible mechanism by which some centenarians, despite onset of chronic disease before the age of 80 years, live exceptionally long.

      How Is Exceptional Longevity Achieved?

      Empirical and other evidence suggest that several strategies can be employed to positively influence health and life span, including dietary modification (eg, moderate caloric restriction) to achieve and maintain ideal weight, exercise, healthy behaviors, avoidance of smoking and excessive drinking, active engagement, and development of social networks and support systems. It is widely accepted that poor health behaviors account for a large proportion of disease burden and contribute to premature death, with 40% of preventable deaths in the United States attributable to behavioral patterns.
      • Schroeder S.A.
      Shattuck Lecture: We can do better—improving the health of the American people.
      • McGinnis J.M.
      • Foege W.H.
      Actual causes of death in the United States.
      Caloric restriction effectively retards the aging phenotype in mammals, as shown by abundant studies.
      • Masoro E.J.
      Caloric restriction and aging: controversial issues.
      Reduced caloric intake ranging from 30% to 60% extends mean and maximum life span. This effect has been reproduced in controlled studies in numerous species including worms, flies, fish, rodents, and nonhuman primates. A 20-year longitudinal adult-onset caloric restriction study in rhesus monkeys found that moderate reduction in dietary intake reduced age-associated deaths and delayed the onset of diabetes, cancer, cardiovascular disease, and brain atrophy.
      • Colman R.J.
      • Anderson R.M.
      • Johnson S.C.
      • et al.
      Caloric restriction delays disease onset and mortality in rhesus monkeys.
      However, in a second study in nonhuman primates in which the control group was fed an apportioned diet to prevent obesity (as opposed to ad libitum feeding), there was no survival advantage with caloric restriction.
      • Mattison J.A.
      • Roth G.S.
      • Beasley T.M.
      • et al.
      Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study.
      There were, however, delays in cancer and diabetes in the dietary restriction groups in both studies.
      Short-term caloric restriction in humans improves surrogate markers of delayed aging such as serum glucose and insulin levels.
      • Ingram D.K.
      • Anson R.M.
      • de Cabo R.
      • et al.
      Development of calorie restriction mimetics as a prolongevity strategy.
      • Lane M.A.
      • de Cabo R.
      • Mattison J.
      • Anson R.M.
      • Roth G.S.
      • Ingram D.K.
      The Roy Walford legacy: diet restriction from molecules to mice to monkeys to man and onto mimetics.
      The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy-2 study, a 2-year randomized controlled trial of calorie restriction in humans, randomized nonobese adults to 25% caloric restriction (11.7% restriction was achieved) or to maintenance of current diet for 2 years.
      • Das S.K.
      • Roberts S.B.
      • Bhapkar M.V.
      • et al.
      CALERIE-2 Study Group
      Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: a 2-y randomized controlled trial of calorie restriction in nonobese humans.
      • Rickman A.D.
      • Williamson D.A.
      • Martin C.K.
      • et al.
      The CALERIE Study: design and methods of an innovative 25% caloric restriction intervention.
      • Rochon J.
      • Bales C.W.
      • Ravussin E.
      • et al.
      CALERIE Study Group
      Design and conduct of the CALERIE study: comprehensive assessment of the long-term effects of reducing intake of energy.
      Biomarker data were applied to 2 biological age algorithms, both of which revealed that reduced caloric intake retarded aging independent of weight reduction.
      • Belsky D.W.
      • Huffman K.M.
      • Pieper C.F.
      • Shalev I.
      • Kraus W.E.
      Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank analysis.
      Although reduced intake of calories in adults improves metabolic and hormonal profiles as well as functional capability, the specific reduction in caloric intake or the requisite body fat mass that improves human health and maximizes life span remains unknown.
      • Fontana L.
      • Klein S.
      Aging, adiposity, and calorie restriction.
      • Heilbronn L.K.
      • de Jonge L.
      • Frisard M.I.
      • et al.
      Pennington CALERIE Team
      Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial.
      Fontana et al
      • Fontana L.
      • Villareal D.T.
      • Weiss E.P.
      • et al.
      Washington University School of Medicine CALERIE Group
      Calorie restriction or exercise: effects on coronary heart disease risk factors; a randomized, controlled trial.
      found that calorie restriction (20% decrease in calories) substantially improved the main risk factors for coronary artery disease in normal-weight and overweight middle-aged adults, and these benefits were similar to the effects of a 20% augmentation in energy expenditure achieved by physical activity.
      Reduced calorie intake retards aging and its processes only when such reduction, in all likelihood, is quite substantial. As such, this strategy may not be a feasible regimen in all but a very small fraction of the population who, like Okinawans, have incorporated dietary moderation as one of several cultural mores of health living. Therefore, it will become necessary to define the mechanism(s) by which caloric restriction alters age-dependent processes that cause functional decline. Thus far, studies in aging models do not demonstrate a beneficial effect of dietary enrichment with antioxidants on median or maximum life span. The longevity benefits of dietary restriction in those with normal BMI are unclear, as are the benefits of supplemental antioxidants or other dietary interventions.
      Regular physical activity promotes healthy human life span, but it is still uncertain whether such activity increases maximum longevity.
      • Stessman J.
      • Hammerman-Rozenberg R.
      • Cohen A.
      • Ein-Mor E.
      • Jacobs J.M.
      Physical activity, function, and longevity among the very old.
      • van Saase J.L.
      • Noteboom W.M.
      • Vandenbroucke J.P.
      Longevity of men capable of prolonged vigorous physical exercise: a 32 year follow up of 2259 participants in the Dutch eleven cities ice skating tour.
      Normal body weight confers the most protection from mortality. All-cause mortality is increased in white adults who are overweight and obese (and possibly underweight)
      • Berrington de Gonzalez A.
      • Hartge P.
      • Cerhan J.R.
      • et al.
      Body-mass index and mortality among 1.46 million white adults.
      and is usually at its lowest when BMI ranges between 20.0 to 24.9 kg/m2.
      • Berrington de Gonzalez A.
      • Hartge P.
      • Cerhan J.R.
      • et al.
      Body-mass index and mortality among 1.46 million white adults.
      Increased physical activity is associated with improved life expectancy, with a benefit of 4.5 years at the highest activity level of 22.5 metabolic equivalent hours per week or more, equal to vigorous walking for at least 450 minutes per week.
      • Moore S.C.
      • Patel A.V.
      • Matthews C.E.
      • et al.
      Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis.
      Continual activity (>7.5 metabolic equivalent h/wk) and a normal weight (BMI, 18.5-24.9 kg/m2) are associated with an added 7.2 years of life compared with inactivity and obesity (BMI, ≥35.0 kg/m2).
      • Moore S.C.
      • Patel A.V.
      • Matthews C.E.
      • et al.
      Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis.
      Increased physical activity promotes life expectancy irrespective of BMI and is a dominant factor in benefiting survival and healthy life in adults over the age of 74 years.
      • Hirsch C.H.
      • Diehr P.
      • Newman A.B.
      • et al.
      Physical activity and years of healthy life in older adults: results from the Cardiovascular Health Study.
      Studies also suggest that active engagement and development of social networks and support systems confer longevity benefits. For example, lack of strong social relations is associated with a mortality risk roughly equivalent to smoking.
      • Holt-Lunstad J.
      • Smith T.B.
      • Layton J.B.
      Social relationships and mortality risk: a meta-analytic review.
      Conversely, a high purpose in life is attended by less impairment in cognitive function and less disability.
      • Boyle P.A.
      • Buchman A.S.
      • Bennett D.A.
      Purpose in life is associated with a reduced risk of incident disability among community-dwelling older persons.
      • Boyle P.A.
      • Buchman A.S.
      • Barnes L.L.
      • Bennett D.A.
      Effect of a purpose in life on risk of incident Alzheimer disease and mild cognitive impairment in community-dwelling older persons.
      Productive engagement, even when targeted as a short-term intervention, can lead to a significant improvement in episodic memory.
      • Park D.C.
      • Lodi-Smith J.
      • Drew L.
      • et al.
      The impact of sustained engagement on cognitive function in older adults: the Synapse Project.
      These interventions, including dietary modification, exercise, active engagement, and purposeful living, appear to be well-represented among the exceptionally long-lived (Table 1), confirming their relevance in practical application to daily life.

      Measuring Successful Aging

      Valid aging biomarkers, when delineated, would enable the assessment of biological age and life expectancy, the evaluation of strategies intended to retard aging, and the standardization of studies in aging research. Minimal criteria for a biomarker of aging would include (1) existence of a quantitative correlation between the biomarker and the age of individuals, (2) evidence suggesting the parameter is not altered with a disease process, (3) evidence that an age-associated change in the putative biomarker is not due to confounding effects of metabolic or nutritional changes, and (4) demonstration that factors that influence the aging rate also alter the putative biomarker.
      • Mooradian A.D.
      Biomarkers of aging: do we know what to look for?.
      However, the development of these minimal criteria for validation of biomarkers must be further refined to account for the role of primary aging in chronic disease processes and the use of dietary or other manipulations that may affect primary aging. For example, a biomarker of aging could also be altered with, predict, or even be implicated in specific chronic diseases for which aging represents a major risk factor. Also, given that many nutritional interventions can alter biological aging processes, such biomarkers of aging would also be altered. Moreover, alterations in such biomarkers with caloric restriction, and with drugs that affect senescence mechanisms, could provide additional support that a given biomarker is reflective of aging.
      Diverse structural and physiologic alterations occur with age, some of which may be deleterious and cause functional decline. These alterations may be due to aging itself, superimposed diseases, the effect of toxicants, adaptive and maladaptive responses, physiologic deficits, or some combination of these influences. A challenge of basic gerontological research is to delineate those phenotypic features and processes in aged individuals that, directly or indirectly, reflect aging per se and constitute primary aging phenomena.
      Some characteristics proposed as being common to human aging include increase in postmaturation mortality (eg, steep drop-off in survival with age), altered chemical constituents in tissues (eg, increased amounts of lipofuscin and cross-linked extracellular matrix proteins), impaired organ function (eg, glomerular filtration rate), impaired organ adaptation to diverse stress (eg, impaired “first-pass” metabolism by the liver, reduced hemodynamic responses to exercise), and rising incidence of assorted diseases (eg, osteoporosis, Alzheimer disease).
      • Cristofalo V.J.
      • Gerhard G.S.
      • Pignolo R.J.
      Molecular biology of aging.
      These “characteristics” of aging, although widely found, have exceptions that call into question their relevance to primary aging processes and their use as biomarkers for aging.
      • Cristofalo V.J.
      • Gerhard G.S.
      • Pignolo R.J.
      Molecular biology of aging.
      For example, alterations in chemical constituents of tissues, impaired physiologic function, and maladaptive responses to stress vary among organs in a given individual as well as among individuals. Although disease-specific mortality increases with age, it has been estimated that the abrogation of mortality caused by atherosclerosis and cancer would lengthen average life span by no more than a decade and would not increase maximum life span. In addition, recent evidence suggests that mortality risk continues to rise even at extremely advanced old age, findings that oppose the conventional view that mortality rates flatten at very advanced ages.
      • Gavrilov L.A.
      • Gavrilova N.S.
      New developments in the biodemography of aging and longevity.
      Putative biomarkers of primary aging may also represent possible predictors of longevity
      • Terry D.F.
      • Wilcox M.A.
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      • et al.
      Lower all-cause, cardiovascular, and cancer mortality in centenarians' offspring.
      • Amara C.E.
      • Koval J.J.
      • Paterson D.H.
      • Cunningham D.A.
      Lung function in older humans: the contribution of body composition, physical activity and smoking.
      • Atkins J.L.
      • Pilling L.C.
      • Ble A.
      • et al.
      Longer-lived parents and cardiovascular outcomes: 8-year follow-up in 186,000 U.K. Biobank participants.
      • Belsky D.W.
      • Caspi A.
      • Houts R.
      • et al.
      Quantification of biological aging in young adults.
      • Boucher N.
      • Dufeu-Duchesne T.
      • Vicaut E.
      • Farge D.
      • Effros R.B.
      • Schachter F.
      CD28 expression in T cell aging and human longevity.
      • Brown D.C.
      • Hayward M.D.
      • Montez J.K.
      • Hummer R.A.
      • Chiu C.T.
      • Hidajat M.M.
      The significance of education for mortality compression in the United States.
      • Campa D.
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      • et al.
      Bitter taste receptor polymorphisms and human aging.
      • Cypel M.C.
      • Salomão S.R.
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      Vision status, ophthalmic assessment, and quality of life in the very old.
      • Deelen J.
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      Employing biomarkers of healthy ageing for leveraging genetic studies into human longevity.
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      • Maier A.B.
      • Hähnel K.
      • et al.
      Lower proportion of naive peripheral CD8+ T cells and an unopposed pro-inflammatory response to human Cytomegalovirus proteins in vitro are associated with longer survival in very elderly people.
      • Diehr P.
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      Predicting future years of life, health, and functional ability: a healthy life calculator for older adults.
      • Dutta A.
      • Henley W.
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      • Wallace R.B.
      • Melzer D.
      Longer lived parents: protective associations with cancer incidence and overall mortality.
      • Frasca D.
      • Diaz A.
      • Romero M.
      • Blomberg B.B.
      The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations.
      • Genther D.J.
      • Betz J.
      • Pratt S.
      • et al.
      Health ABC Study
      Association of hearing impairment and mortality in older adults.
      • Gill T.M.
      • Allore H.G.
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      • Guo Z.
      Hospitalization, restricted activity, and the development of disability among older persons.
      • Grzegorczyk P.B.
      • Jones S.W.
      • Mistretta C.M.
      Age-related differences in salt taste acuity.
      • Hays N.P.
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      Metabolic aging and predicted longevity: results of a cross-sectional study in post-menopausal women.
      • He Q.
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      • Grove J.S.
      • et al.
      Shorter men live longer: association of height with longevity and FOXO3 genotype in American men of Japanese ancestry.
      • Hennis A.
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      • Leske M.C.
      the Barbados Eye Study Group
      Lens opacities and mortality: the Barbados Eye Studies.
      • Hirotomi T.
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      • Ogawa H.
      • Miyazaki H.
      Number of teeth and 5-year mortality in an elderly population.
      • Holtzer R.
      • Wang C.
      • Lipton R.
      • Verghese J.
      The protective effects of executive functions and episodic memory on gait speed decline in aging defined in the context of cognitive reserve.
      • Humes L.E.
      • Kewley-Port D.
      • Fogerty D.
      • Kinney D.
      Measures of hearing threshold and temporal processing across the adult lifespan.
      • Kaye J.A.
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      • Holm L.A.
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      Neurologic evaluation of the optimally healthy oldest old.
      • Kopecek M.
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      • Sulc Z.
      • Lukavsky J.
      • Stepankova H.
      Montreal Cognitive Assessment and Mini-Mental State Examination reliable change indices in healthy older adults.
      • Lambert N.D.
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      • Pankratz V.S.
      • Jacobson R.M.
      • Poland G.A.
      Understanding the immune response to seasonal influenza vaccination in older adults: a systems biology approach.
      • Lemez S.
      • Wattie N.
      • Baker J.
      Do “big guys” really die younger? an examination of height and lifespan in former professional basketball players.
      • Matsuyama Y.
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      Dental status and compression of life expectancy with disability.
      • McKibbin M.
      • Mohammed M.
      • James T.E.
      • Atkinson P.L.
      Short-term mortality among middle-aged cataract surgery patients.
      • Montez J.K.
      • Hayward M.D.
      Cumulative childhood adversity, educational attainment, and active life expectancy among U.S. adults.
      • Morrisette-Thomas V.
      • Cohen A.A.
      • Fülöp T.
      • et al.
      Inflamm-aging does not simply reflect increases in pro-inflammatory markers.
      • Nakamoto M.
      • Otsuka R.
      • Yuki A.
      • et al.
      Higher gait speed and smaller sway area decrease the risk for decline in higher-level functional capacity among middle-aged and elderly women.
      • Newman J.C.
      • Milman S.
      • Hashmi S.K.
      • et al.
      Strategies and challenges in clinical trials targeting human aging.
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      • et al.
      Association between lens opacities and mortality in the Priverno Eye Study.
      • Peters M.J.
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      The transcriptional landscape of age in human peripheral blood.
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      Improvement in activities of daily living among Danish centenarians? a comparative study of two centenarian cohorts born 20 years apart.
      • Sanders J.L.
      • Ding V.
      • Arnold A.M.
      • et al.
      Do changes in circulating biomarkers track with each other and with functional changes in older adults?.
      • Sansoni P.
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      • Fagnoni F.
      • et al.
      The immune system in extreme longevity.
      • Seow Y.X.
      • Ong P.K.
      • Huang D.
      Odor-specific loss of smell sensitivity with age as revealed by the Specific Sensitivity test.
      • Sridhar S.
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      • Srikanthan P.
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      Muscle mass index as a predictor of longevity in older adults.
      • Stessman J.
      • Rottenberg Y.
      • Fischer M.
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      • Jacobs J.M.
      Handgrip strength in old and very old adults: mood, cognition, function, and mortality.
      • Stijntjes M.
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      Familial longevity is marked by better cognitive performance at middle age: the Leiden Longevity Study.
      • Strindhall J.
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      No Immune Risk Profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study.
      • Taekema D.G.
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      • Maier A.B.
      Predicting survival in oldest old people.
      • Tanisawa K.
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      • et al.
      Inverse association between height-increasing alleles and extreme longevity in Japanese women.
      • Tomioka K.
      • Kurumatani N.
      • Hosoi H.
      Relationship of having hobbies and a purpose in life with mortality, activities of daily living, and instrumental activities of daily living among community-dwelling elderly adults.
      • Venturelli M.
      • Schena F.
      • Scarsini R.
      • Muti E.
      • Richardson R.S.
      Limitations to exercise in female centenarians: evidence that muscular efficiency tempers the impact of failing lungs.
      • Verghese J.
      • Holtzer R.
      • Lipton R.B.
      • Wang C.
      Mobility stress test approach to predicting frailty, disability, and mortality in high-functioning older adults.
      • Waaijer M.E.
      • Gunn D.A.
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      • et al.
      p16INK4a Positive cells in human skin are indicative of local elastic fiber morphology, facial wrinkling, and perceived age.
      • Waaijer M.E.
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      • et al.
      The number of p16INK4a positive cells in human skin reflects biological age.
      • Waaijer M.E.
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      • Goldeck D.
      • et al.
      Assessment of health status by molecular measures in adults ranging from middle-aged to old: ready for clinical use?.
      • Wikby A.
      • Månsson I.A.
      • Johansson B.
      • Strindhall J.
      • Nilsson S.E.
      The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20-100 years of age.
      (Table 2). Each measurement has its limitations as a reliable biomarker for aging and longevity. Some biomarkers have relevance to both biological and functional aspects of exceptional longevity, including gait speed and preservation of ability to perform ADLs. Other biomarkers are biochemical measurements used in clinical practice that in combination have value in estimating biological age. Some are system-specific measurements that are likely surrogates for overall health. Many are more speculative and require further investigation.
      Table 2Putative Biomarkers of Primary Aging Processes and Longevity
      BiomarkerReference
      Disease-free survival or disability-free survival at 6-month intervals
      • Newman J.C.
      • Milman S.
      • Hashmi S.K.
      • et al.
      Strategies and challenges in clinical trials targeting human aging.
      Time to impairment in the next activity of daily living
      • Newman J.C.
      • Milman S.
      • Hashmi S.K.
      • et al.
      Strategies and challenges in clinical trials targeting human aging.
      Length of stay after hospitalization
      • Gill T.M.
      • Allore H.G.
      • Holford T.R.
      • Guo Z.
      Hospitalization, restricted activity, and the development of disability among older persons.
      Height, especially in men
      • He Q.
      • Morris B.J.
      • Grove J.S.
      • et al.
      Shorter men live longer: association of height with longevity and FOXO3 genotype in American men of Japanese ancestry.
      ,
      • Lemez S.
      • Wattie N.
      • Baker J.
      Do “big guys” really die younger? an examination of height and lifespan in former professional basketball players.
      ,
      • Tanisawa K.
      • Hirose N.
      • Arai Y.
      • et al.
      Inverse association between height-increasing alleles and extreme longevity in Japanese women.
      Facial features
      • Belsky D.W.
      • Caspi A.
      • Houts R.
      • et al.
      Quantification of biological aging in young adults.
      Gait speed, grip strength, muscle mass, mobility stress test
      • Nakamoto M.
      • Otsuka R.
      • Yuki A.
      • et al.
      Higher gait speed and smaller sway area decrease the risk for decline in higher-level functional capacity among middle-aged and elderly women.
      ,
      • Srikanthan P.
      • Karlamangla A.S.
      Muscle mass index as a predictor of longevity in older adults.
      ,
      • Stessman J.
      • Rottenberg Y.
      • Fischer M.
      • Hammerman-Rozenberg A.
      • Jacobs J.M.
      Handgrip strength in old and very old adults: mood, cognition, function, and mortality.
      ,
      • Taekema D.G.
      • Gussekloo J.
      • Westendorp R.G.
      • de Craen A.J.
      • Maier A.B.
      Predicting survival in oldest old people.
      ,
      • Verghese J.
      • Holtzer R.
      • Lipton R.B.
      • Wang C.
      Mobility stress test approach to predicting frailty, disability, and mortality in high-functioning older adults.
      Daily and instrumental activities of daily living
      • Diehr P.
      • Diehr M.
      • Arnold A.
      • et al.
      Predicting future years of life, health, and functional ability: a healthy life calculator for older adults.
      ,
      • Rasmussen S.H.
      • Thinggaard M.
      • Højgaard M.B.
      • Jeune B.
      • Christensen K.
      • Andersen-Ranberg K.
      Improvement in activities of daily living among Danish centenarians? a comparative study of two centenarian cohorts born 20 years apart.
      ,
      • Tomioka K.
      • Kurumatani N.
      • Hosoi H.
      Relationship of having hobbies and a purpose in life with mortality, activities of daily living, and instrumental activities of daily living among community-dwelling elderly adults.
      Cognitive tests such as the Digit Symbol Substitution Test or Montreal Cognitive Test
      • Holtzer R.
      • Wang C.
      • Lipton R.
      • Verghese J.
      The protective effects of executive functions and episodic memory on gait speed decline in aging defined in the context of cognitive reserve.
      ,
      • Kopecek M.
      • Bezdicek O.
      • Sulc Z.
      • Lukavsky J.
      • Stepankova H.
      Montreal Cognitive Assessment and Mini-Mental State Examination reliable change indices in healthy older adults.
      ,
      • Sanders J.L.
      • Ding V.
      • Arnold A.M.
      • et al.
      Do changes in circulating biomarkers track with each other and with functional changes in older adults?.
      ,
      • Stijntjes M.
      • de Craen A.J.
      • van Heemst D.
      • et al.
      Familial longevity is marked by better cognitive performance at middle age: the Leiden Longevity Study.
      Blood glucose or hemoglobin A1c, hypertension and elevated lipids, interleukin 6, insulin-like growth factor 1, and insulin-like growth factor binding proteins
      • Deelen J.
      • van den Akker E.B.
      • Trompet S.
      • et al.
      Employing biomarkers of healthy ageing for leveraging genetic studies into human longevity.
      ,
      • Morrisette-Thomas V.
      • Cohen A.A.
      • Fülöp T.
      • et al.
      Inflamm-aging does not simply reflect increases in pro-inflammatory markers.
      ,
      • Sanders J.L.
      • Ding V.
      • Arnold A.M.
      • et al.
      Do changes in circulating biomarkers track with each other and with functional changes in older adults?.
      ,
      • Waaijer M.E.
      • Westendorp R.G.
      • Goldeck D.
      • et al.
      Assessment of health status by molecular measures in adults ranging from middle-aged to old: ready for clinical use?.
      CD4+, CD28 and CD8+, CD28 T cells; percentage of T cells that are naive vs memory (CD4 cells, CD8 cells)
      • Boucher N.
      • Dufeu-Duchesne T.
      • Vicaut E.
      • Farge D.
      • Effros R.B.
      • Schachter F.
      CD28 expression in T cell aging and human longevity.
      ,
      • Derhovanessian E.
      • Maier A.B.
      • Hähnel K.
      • et al.
      Lower proportion of naive peripheral CD8+ T cells and an unopposed pro-inflammatory response to human Cytomegalovirus proteins in vitro are associated with longer survival in very elderly people.
      ,
      • Sansoni P.
      • Vescovini R.
      • Fagnoni F.
      • et al.
      The immune system in extreme longevity.
      ,
      • Strindhall J.
      • Nilsson B.O.
      • Löfgren S.
      • et al.
      No Immune Risk Profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study.
      ,
      • Wikby A.
      • Månsson I.A.
      • Johansson B.
      • Strindhall J.
      • Nilsson S.E.
      The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20-100 years of age.
      Antibody response to annual influenza vaccination; delayed hypersensitivity skin test
      • Frasca D.
      • Diaz A.
      • Romero M.
      • Blomberg B.B.
      The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations.
      ,
      • Hays N.P.
      • Bathalon G.P.
      • Meydani S.N.
      • et al.
      Metabolic aging and predicted longevity: results of a cross-sectional study in post-menopausal women.
      ,
      • Lambert N.D.
      • Ovsyannikova I.G.
      • Pankratz V.S.
      • Jacobson R.M.
      • Poland G.A.
      Understanding the immune response to seasonal influenza vaccination in older adults: a systems biology approach.
      ,
      • Sridhar S.
      • Begom S.
      • Hoschler K.
      • et al.
      Longevity and determinants of protective humoral immunity after pandemic influenza infection.
      Cataracts
      • Cypel M.C.
      • Salomão S.R.
      • Dantas P.E.C.
      • et al.
      Vision status, ophthalmic assessment, and quality of life in the very old.
      ,
      • Hennis A.
      • Wu S.Y.
      • Li X.
      • Nemesure B.
      • Leske M.C.
      the Barbados Eye Study Group
      Lens opacities and mortality: the Barbados Eye Studies.
      ,
      • McKibbin M.
      • Mohammed M.
      • James T.E.
      • Atkinson P.L.
      Short-term mortality among middle-aged cataract surgery patients.
      ,
      • Nucci C.
      • Cedrone C.
      • Culasso F.
      • et al.
      Association between lens opacities and mortality in the Priverno Eye Study.
      Threshold for hearing high-pitched tones; tests of taste and smell
      • Campa D.
      • De Rango F.
      • Carrai M.
      • et al.
      Bitter taste receptor polymorphisms and human aging.
      ,
      • Genther D.J.
      • Betz J.
      • Pratt S.
      • et al.
      Health ABC Study
      Association of hearing impairment and mortality in older adults.
      ,
      • Grzegorczyk P.B.
      • Jones S.W.
      • Mistretta C.M.
      Age-related differences in salt taste acuity.
      ,
      • Humes L.E.
      • Kewley-Port D.
      • Fogerty D.
      • Kinney D.
      Measures of hearing threshold and temporal processing across the adult lifespan.
      ,
      • Seow Y.X.
      • Ong P.K.
      • Huang D.
      Odor-specific loss of smell sensitivity with age as revealed by the Specific Sensitivity test.
      Tests of proprioception and balance
      • Kaye J.A.
      • Oken B.S.
      • Howieson D.B.
      • Howieson J.
      • Holm L.A.
      • Dennison K.
      Neurologic evaluation of the optimally healthy oldest old.
      Forced expiratory volume in 1 second
      • Amara C.E.
      • Koval J.J.
      • Paterson D.H.
      • Cunningham D.A.
      Lung function in older humans: the contribution of body composition, physical activity and smoking.
      ,
      • Venturelli M.
      • Schena F.
      • Scarsini R.
      • Muti E.
      • Richardson R.S.
      Limitations to exercise in female centenarians: evidence that muscular efficiency tempers the impact of failing lungs.
      Number of remaining teeth
      • Hirotomi T.
      • Yoshihara A.
      • Ogawa H.
      • Miyazaki H.
      Number of teeth and 5-year mortality in an elderly population.
      ,
      • Matsuyama Y.
      • Aida J.
      • Watt R.G.
      • et al.
      Dental status and compression of life expectancy with disability.
      One or two parents reaching 90 years of age
      • Terry D.F.
      • Wilcox M.A.
      • McCormick M.A.
      • et al.
      Lower all-cause, cardiovascular, and cancer mortality in centenarians' offspring.
      ,
      • Atkins J.L.
      • Pilling L.C.
      • Ble A.
      • et al.
      Longer-lived parents and cardiovascular outcomes: 8-year follow-up in 186,000 U.K. Biobank participants.
      ,
      • Dutta A.
      • Henley W.
      • Robine J.M.
      • Langa K.M.
      • Wallace R.B.
      • Melzer D.
      Longer lived parents: protective associations with cancer incidence and overall mortality.
      Educational attainment
      • Brown D.C.
      • Hayward M.D.
      • Montez J.K.
      • Hummer R.A.
      • Chiu C.T.
      • Hidajat M.M.
      The significance of education for mortality compression in the United States.
      ,
      • Montez J.K.
      • Hayward M.D.
      Cumulative childhood adversity, educational attainment, and active life expectancy among U.S. adults.
      More speculative: DNA methylation indices; senescent cell burden
      • Peters M.J.
      • Joehanes R.
      • Pilling L.C.
      • et al.
      The transcriptional landscape of age in human peripheral blood.
      ,
      • Waaijer M.E.
      • Gunn D.A.
      • Adams P.D.
      • et al.
      p16INK4a Positive cells in human skin are indicative of local elastic fiber morphology, facial wrinkling, and perceived age.
      ,
      • Waaijer M.E.
      • Parish W.E.
      • Strongitharm B.H.
      • et al.
      The number of p16INK4a positive cells in human skin reflects biological age.
      Inclusion of centenarians in biomarker studies offers the possibility of developing measurements that can identify successful (biological) aging even before extreme longevity is reached. These studies may also implicate pathways that help to define mechanisms that link current health status to exceptional long life.
      • Arai Y.
      • Martin-Ruiz C.M.
      • Takayama M.
      • et al.
      Inflammation, but not telomere length, predicts successful ageing at extreme old age: a longitudinal study of semi-supercentenarians.
      • Collino S.
      • Montoliu I.
      • Martin F.P.
      • et al.
      Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism.
      • Hausman D.B.
      • Fischer J.G.
      • Johnson M.A.
      Protein, lipid, and hematological biomarkers in centenarians: definitions, interpretation and relationships with health.
      • Horvath S.
      • Pirazzini C.
      • Bacalini M.G.
      • et al.
      Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring.
      • Sanchis-Gomar F.
      • Pareja-Galeano H.
      • Santos-Lozano A.
      • et al.
      A preliminary candidate approach identifies the combination of chemerin, fetuin-A, and fibroblast growth factors 19 and 21 as a potential biomarker panel of successful aging.
      There are multiple pathways to exceptional longevity (Figure 3). Based on existing data, possible relationships among factors associated with extremely long life likely account for both the attainment of long life and the heterogeneity of centenarians (Figure 3). For example, an individual who achieves exceptional longevity by escaping from age-onset disease may do so through genetic mechanism(s), dietary practices and exercise, or through some combination of these influences. Conversely, an individual who achieves exceptional longevity through survival from age-onset disease may do so through as yet poorly understood resiliency pathways.
      Figure thumbnail gr3
      Figure 3Multiple pathways to exceptional longevity. Shown are putative relationships among factors associated with extreme long life.
      Measuring biomarkers of aging in younger cohorts obviates the confounders of chronic disease. In the Dunedin Study (New Zealand) that follows a 1972-1973 birth cohort, assessment of balance, grip strength, motor function, physical disability, cognitive function, facial aging, clinical laboratory tests, cognitive decline, and self-rated health was undertaken.
      • Belsky D.W.
      • Caspi A.
      • Houts R.
      • et al.
      Quantification of biological aging in young adults.
      The rate of functional decline in diverse organs was used to determine biological aging in young individuals in whom age-related diseases were not present. Interestingly, “biological aging” varied in a normal distribution among similarly aged individuals in this cohort.
      • Belsky D.W.
      • Caspi A.
      • Houts R.
      • et al.
      Quantification of biological aging in young adults.

      Implications of Exceptional Longevity

      Individuals with extended life expectancy, and especially those with exceptional longevity, demonstrate compression of disability and support that trends of increasing life expectancy need not be associated with greater morbidity. Observations in long-lived individuals suggest lifestyle strategies that promote independence, health span extension, and perhaps even life span extension. Identification and measurement of biomarkers associated with longevity will permit more accurate estimates of biological age that will inform better guidance for appropriate health screening as well as guidance for anticipatory health discussions.
      Several algorithms have been proposed to estimate biological age.
      • Waaijer M.E.
      • Westendorp R.G.
      • Goldeck D.
      • et al.
      Assessment of health status by molecular measures in adults ranging from middle-aged to old: ready for clinical use?.
      • Belsky D.W.
      • Moffitt T.E.
      • Cohen A.A.
      • et al.
      Eleven telomere, epigenetic clock, and biomarker-composite quantifications of biological aging: do they measure the same thing?.
      • Arbeev K.G.
      • Cohen A.A.
      • Arbeeva L.S.
      • et al.
      Optimal versus realized trajectories of physiological dysregulation in aging and their relation to sex-specific mortality risk.
      • Levine M.E.
      Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age?.
      Those based on functional as well as biochemical and other measurements may be more likely to capture key elements associated with prediction of extreme longevity. An unresolved issue relates to disagreement between person-level vs population-level measures, and better resolution of person-level changes awaits further investigations.
      Historically, guidance on appropriate health screening has not accounted for differences between chronological and biological age, and thus screening may be overlooked for individuals with predicted longer life or pursued in those with shorter expected life spans.
      The utility and role of screening tests in older adults are currently unresolved. There is a need for guidelines regarding individualized screening decisions in older people, which may have greater utility than those based on age alone. A framework that takes into account estimates of life expectancy, risk of cause-specific mortality, and recognized screening outcomes would yield potential benefits to screening. Walter and Covinsky
      • Walter L.C.
      • Covinsky K.E.
      Cancer screening in elderly patients: a framework for individualized decision making.
      found that with respect to cancer screening, potential benefits to screening varied substantially for similarly aged patients with different life expectancies. One conclusion drawn by this approach is that cancer screening fails to confer any benefit when life expectancy is less than 5 years.
      Better estimates of individualized life expectancy through clinical and other measures of biological aging would thus contribute to screening decisions in older adults. For example, a validated mortality index has been used to create a life expectancy calculator that incorporates patient-level risk factors. Such a calculator may aid clinicians in deciding on relevant preventive interventions for their older patients.
      • Lee S.J.
      • Boscardin W.J.
      • Kirby K.A.
      • Covinsky K.E.
      Individualizing life expectancy estimates for older adults using the Gompertz Law of Human Mortality.

      Conclusion

      The bases of extreme long life are multifactorial and are contributed to by genetic disposition and especially environmental influences that vary with culture and geography. Characteristics of aging are heterogeneous, even among long-lived individuals. Associations between specific clinical or genetic biomarkers exist, but thus far there is no single biomarker predictive of long life. Careful observations in the oldest old offer empirical strategies that favor increased health span and life span, with implications for compression of disability, identification and implementation of lifestyle behaviors that promote independence, and better clinical decision making by assessment of biological age.

      Acknowledgments

      I thank Dr Karl Nath for his careful review of the submitted manuscript and thoughtful editorial suggestions.

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