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Correspondence: Address to Robert J. Pignolo, MD, PhD, Division of Geriatric Medicine and Gerontology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
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.
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.
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Characteristics of aging are heterogeneous, even among long-lived individuals.
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Associations between specific clinical or genetic biomarkers exist, but there is unlikely to be a single biomarker predictive of long life.
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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
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
Although human life expectancy and median length of life rose dramatically over the past century, maximum life span has remained largely unchanged (Figure 1).
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.
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.
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,
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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 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' “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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Resistance to stressors and disease that contributes to healthy aging is often described in the context of psychological resiliency, such as reduction of depression.
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.
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,
There are likely direct relationships among resiliency against physical and physiologic stressors, homeostatic resistance mechanisms against aging-related, system-specific dysfunction, and longevity.
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.
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.
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.
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.
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.
Biomarker data were applied to 2 biological age algorithms, both of which revealed that reduced caloric intake retarded aging independent of weight reduction.
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.
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.
JAMA.2006; 295 ([published correction appears in JAMA. 2006;295(21):2482]): 1539-1548
Washington University School of Medicine CALERIE Group Calorie restriction or exercise: effects on coronary heart disease risk factors; a randomized, controlled trial.
Am J Physiol Endocrinol Metab.2007; 293: E197-E202
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.
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)
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.
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).
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.
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.
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.
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).
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.
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.
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.
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.
(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
Biomarker
Reference
Disease-free survival or disability-free survival at 6-month intervals
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.
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.
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.
Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism.
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 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.
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.
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.
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
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.
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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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.
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.
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.
Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial.
JAMA.2006; 295 ([published correction appears in JAMA. 2006;295(21):2482]): 1539-1548
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.
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.
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