Exceptional Longevity Research Articles

Demographic and Anthropometric Variables Related to Longevity: Results from a Greek Centenarians’ Study

Centenarian research contributes to expanding our knowledge on longevity and healthy aging. In Greece, a variety of studies have been conducted in order to explore exceptional longevity. This is a retrospective study of 106 centenarians employing both quantitative and qualitative measures in order to explore centenarians own perspective on longevity. Basic socio demographic and life style variables where associated with centenarians beliefs and perceptions about their longevity. The majority of centenarians attributed their longevity to God and to living a good life overall. God and social networks were reported as their main source of strength in order to continue living. Gender differences were also evident as male centenarians reported non abusive behaviors and a sense of having a measure in daily living, as well as nutrition as their main source of longevity, while female emphasized on God and social networks. Gender differences on Body Mass Index and Smoking are also evident. Centenarians own perception of longevity could be further explored and findings could be incorporated in future research and intervention programs aiming at healthy longevity.

The thyroid gland and the process of aging

The endocrine organs, including the thyroid gland, undergo important functional changes during aging. It is known that the prevalence of thyroid disorders increases with age. Importantly, subclinical disturbances of thyroid function are more frequent than overt diseases in the elderly. Moreover, the clinical course of thyroid diseases in elderly people differs from that observed in younger subjects; namely, symptoms are more subtle and are often attributed to normal aging, and therefore, require special attention in elderly individuals. One of the subclinical thyroid function disturbances is subclinical hypothyroidism, which is characterized by normal free thyroxine (FT4) and increased thyrotropin (TSH) levels. The prevalence of subclinical hypothyroidism increases with aging and ranges from 3 to 16 % in individuals aged 60 years and older [1]. In contrast to overt hypothyroidism, the subclinical hypothyroidism in elderly subjects is not associated with impairment of physical and cognitive function, depression, metabolic disturbances or poor quality of life [2,3]. Subclinical hypothyroidism is also not associated with the increased overall mortality risk [2]. Moreover, there is not association between subclinical hypothyroidism and incident coronary heart disease (CHD), heart failure (HF) or cardiovascular (CV) mortality [4]. Similarly, total mortality was not increased in subjects with subclinical hypothyroidism, although the risk of CHD events and of CHD mortality increased with TSH levels 10 mU/L or higher [5]. Importantly, a quite high rate of reversion of subclinical hypothyroidism to euthyroidism in individuals aged at least 65 years with lower baseline TSH levels (4.5-6.9 mU/L) and antithyroid peroxidase antibody (TPOAb) negativity (≤ 37 IU/L) was observed [6]. In turn, higher TSH levels and TPOAb positivity were independently associated with lower chance of reversion to euthyroid status; TSH levels ≥10 mU/L were independently associated with progression to overt hypothyroidism [6]. There are obvious indications for overt hypothyroidism treatment. In turn, indications for treatment of subclinical hypothyroidism are still quite controversial. Nevertheless, the replacement therapy with L-thyroxine is not uniformly recommended in elderly people with subclinical hypothyroidism. For example, L-thyroxine replacement therapy did not improve cognitive function in elderly individuals with subclinical hypothyroidism [7]. Moreover, despite improvement of lipid profile due to treatment of L-thyroxine in subclinical hypothyroidism, there is no clear evidence that this beneficial effect can be associated with decreased cardiovascular or all-cause mortality in elderly patients [8]. Intriguingly, thyroid hypofunction, as well as elevated thyrotropin (TSH) levels may contribute to the extended lifespan. A potential contribution of TSH and thyroid hormones to lifespan regulation was observed in the studies performed on thyroid disease-free population of Ashkenazi Jews, characterized by exceptional longevity (centenarians). For example, the higher serum TSH level in these individuals in comparison with the control groups was observed [9]. Thus, increased serum TSH level seems to be associated with extreme longevity [9]. Moreover, two single nucleotide polymorphisms (SNPs) in TSH receptor (TSHR) gene (namely rs10149689 and rs12050077) were associated with increased TSH level in Ashkenazi Jewish centenarians and their offspring [10]. Also, an inverse correlation between FT4 and TSH levels in centenarians was reported [9] which may suggest a potential role of decreased thyroid function in lifespan regulation, leading to extended longevity. The findings obtained in the Leiden Longevity Study actually show the associations between low thyroid activity and exceptional familial longevity [11]. Also in animals, a reduced thyroid function with low levels of T4 seems to be associated with extended longevity [12-14]. A very severe thyroid hypofunction was observed in Ames dwarf (df/df) mice. These animals are characterized by mutations at the Prop-1 (Prophet of pituitary factor 1) gene and demonstrate a lack of growth hormone (GH), prolactin and TSH. These features may unexpectedly contribute to remarkable longevity in Ames dwarf mice [12]. Furthermore, severe hypothyroid Ames dwarfs and mice with targeted disruption of the growth hormone (GH) receptor/GH binding protein gene (GH receptor knockout; GHRKO) with mild thyroid hypofunction, have decreased thyroid follicle size which may explain decreased thyroid hormone levels in these long-lived mutants [15]. In conclusion, the altered thyroid function may play, via different mechanisms [16], a relevant role in lifespan regulation. Namely, decreased thyroid function may lead to extended longevity.

Models to explore genetics of human aging.

Genetic studies have bestowed insight into the biological mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms’ aging. Recent advances in molecular and genetic epidemiology provide tools to explore the genetic sources of the variability in biological aging in humans. To be successful, the genetic study of a complex condition such as aging requires the clear definition of essential traits that can characterize the aging process phenotypically. Phenotypes of human aging have long relied on mortality rate or exceptional longevity. Genome-wide association studies (GWAS) have been shown to present an unbiased approach to the identification of new candidate genes for human diseases. The GWAS approach can also be used for positive health phenotypes such as longevity or a delay in age-related chronic disease, as well as for other age related changes such as loss of telomere length or lens transparency. Sequencing, either in targeted regions or across the whole genome can further identify rare variation that may contribute to the biological aging mechanisms. To date, the results of the GWAS for longevity are rather disappointing, possibly in part due to the small number of individuals with GWAS data who have reached advanced old age.Human aging phenotypes are needed that can be assessed prior to death, and should be both heritable and validated as predictors of longevity. Potentially, phenotypes that focus on “successful” or “healthy” aging will be more powerful as they can be measured in large numbers of people and also are clinically relevant.We postulate that construction of an integrated phenotype of aging can be achieved capitalizing on multiple traits that may have weak correlations, but a shared underlying genetic architecture. This is based on a hypothesis that convergent results from multiple individual aging-related traits will point out the pleiotropic signals responsible for the overall rate of aging of the organism. An approach would be to investigate traits that are linked to the state of many vital functions, disability, and ultimately survival rates, to identify common biological pathways that govern aging processes in humans. New composite aging phenotypes must be validated by predicting all-cause mortality, major chronic disease and disability late in life.

Exome and whole genome sequencing in aging and longevity.

Calendar age is the major risk factor for common disease. It is therefore expected that understanding the aging process will eventually lead to promotion of better health conditions in elderly populations. Such insight may be obtained by identifying the genetic determinants of familial and exceptional longevity and age-related disease. Research of these determinants has been performed in candidate gene, genome-wide association and linkage studies. Because exploration of the common variation in the genome did not explain much of the variation in the rate of aging and longevity, researchers in the field have only recently started to investigate the contribution of rare genetic variants to these traits. The increased throughput and decreased costs of next generation sequencing (NGS) have resulted in a great deal of novel applications for sequencing sets of candidate genes, whole exomes, and whole genomes of individuals. Most of the successful NGS applications are as yet those focused on genetic syndromes and cancers for which causal mutations are readily being identified. In this chapter, we discuss the genetic and phenomic aspects of human aging research and the use of NGS data to identify genes relevant for age-related diseases and lifespan regulation, and to investigate the accumulation of somatic genetic variation during the course of life.

Extended maternal age at birth of last child and women's longevity in the Long Life Family Study.

This study investigated the association between maternal age at birth of last child and likelihood of survival to advanced age. This was a nested case-control study using Long Life Family Study data. Three hundred eleven women who survived past the oldest 5th percentile of survival (according to birth cohort-matched life tables) were identified as cases, and 151 women who died at ages younger than the top 5th percentile of survival were identified as controls. A Bayesian mixed-effect logistic regression model was used to estimate the association between maternal age at birth of last child and exceptional longevity among these 462 women. We found a significant association for older maternal age, whereby women who had their last child beyond age 33 years had twice the odds for survival to the top 5th percentile of survival for their birth cohorts compared with women who had their last child by age 29 years (age between 33 and 37 y: odds ratio, 2.08; 95% CI, 1.13 to 3.92; older age: odds ratio, 1.92; 95% CI, 1.03 to 3.68). This study supports findings from other studies demonstrating a positive association between older maternal age and greater odds for surviving to an unusually old age.

Can enhanced autophagy be associated with human longevity? Serum levels of the autophagy biomarker beclin-1 are increased in healthy centenarians.

Autophagy is a major clearance mechanism that degrades organelles and large protein aggregates to maintain cell survival and protein homeostasis. Although induction of autophagy can promote longevity in experimental models, the question as to whether increased basal levels of autophagy can be associated with human longevity remains open. In this pilot study, we investigated the association between serum concentrations of beclin-1, a key regulator of autophagy, and human exceptional longevity (EL). Serum beclin-1 was measured in three study groups: 79 healthy centenarians (39 males, aged 100-104 years); 178 non-diabetic patients who had experienced an acute myocardial infarction at a young age (101 males, 28-39 years); and 180 age- and sex-matched healthy young volunteers (103 males, 27-39 years) using an enzyme-linked immunosorbent assay. Healthy centenarians had significantly higher beclin-1 levels (2.2±0.8 ng/mL) compared with both young patients with myocardial infarction (1.5±0.7 ng/mL; p<0.001) and healthy controls (1.4±0.9 ng/mL; p<0.001), whereas no significant difference was observed between the two groups of young subjects. The multivariate-adjusted odds ratio for having serum beclin-1 levels >1.5 ng/mL (i.e., 75th percentile of the young controls' levels) was 3.4 (95% confidence interval 1.8-5.7; p<0.001) for healthy centenarians. Our preliminary data suggest that elevated basal levels of autophagy as reflected by high serum beclin-1 levels may be a biomarker of healthy human EL.

Male longevity in Sardinia, a review of historical sources supporting a causal link with dietary factors.

The identification of a hot spot of exceptional longevity, the Longevity Blue Zone (LBZ), in the mountain population of Sardinia has aroused considerable interest toward its traditional food as one of the potential causal factors. This preliminary study on the traditional Sardinian diet has been supported by the literature available, which has been carefully reviewed and compared. Up to a short time ago, the LBZ population depended mostly upon livestock rearing, and consumption of animal-derived foods was relatively higher than in the rest of the island. The nutrition transition (NT) in urbanized and lowland areas began in the mid-1950s, fueled by economic development, whereas in the LBZ it started later owing to prolonged resistance to change by a society organized around a rather efficient pastoral economy. Even nowadays a large proportion of the population in this area still follows the traditional diet based on cereal-derived foods and dairy products. The LBZ cohorts comprising individuals who were of a mature age when NT began may have benefited both from the high-quality, albeit rather monotonous, traditional diet to which they had been exposed most of their life and from the transitional diet, which introduced positive changes such as more variety, increased consumption of fruits and vegetables and moderate meat intake. It could be speculated that these changes may have brought substantial health benefits to this particular aging group, which was in need of nutrient-rich food at this specific time in life, thereby resulting in a decreased mortality risk and, in turn, life-span extension.

Genetic variants associated with lung function: the long life family study.

BackgroundReduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals with exceptional longevity have not been identified.MethodWe conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia. The association between SNPs and FEV1 and FEV1/FVC was analyzed using a linear mixed effects model adjusted for age, age2, sex, height, field center, ancestry principal components and kinship structure to adjust for family relationships separately for ever smokers and never smokers. In the linkage analysis, we used the residuals of the FEV1 and FEV1/FVC, adjusted for age, sex, height, ancestry principal components (PCs), smoking status, pack-years, and field center.ResultsWe identified nine SNPs in strong linkage disequilibrium in the CYP2U1 gene to be associated with FEV1 and a novel SNP (rs889574) associated with FEV1/FVC, none of which were replicated in the CHARGE/SpiroMeta consortia. Using linkage analysis, we identified a novel linkage peak in chromosome 2 at 219 cM for FEV1/FVC (LOD: 3.29) and confirmed a previously reported linkage peak in chromosome 6 at 28 cM (LOD: 3.33) for FEV1.ConclusionFuture studies need to identify the rare genetic variants underlying the linkage peak in chromosome 6 for FEV1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0134-x) contains supplementary material, which is available to authorized users.

PTK2 rs7460 and rs7843014 polymorphisms and exceptional longevity: a functional replication study.

Focal adhesion is critical for cell survival. The focal adhesion kinase (FAK, or PTK2) is an important component of the human interactome and thus is a potential longevity-related protein. Here we studied the association between two PTK2 gene single-nucleotide polymorphisms (SNPs) (rs7843014, rs7460) and exceptional longevity (EL). In addition to gaining insight into their functionality by determining luciferase gene reporter activity, we studied the genotype/allele frequency of these two SNPs among three different cohorts: (1) Spanish centenarians (n=175, 100-111 years, 144 women) and healthy controls (n=355, 20-50 years, 284 women); (2) Italian centenarians (n=79, 100-104 years, 40 women) and controls (n=316, 29-50 years, 156 women); and (3) Japanese centenarians (n=742, 100-116 years, 623 women) and healthy controls (n=499, 23-59 years, 356 women). Both SNPs had functional significance, with the A allele up-regulating luciferase activity compared to the other allele (rs7460 T allele and rs7843014 C allele, respectively). The A allele of both SNPs was negatively associated with EL in the Spanish cohort (rs7460, odds ratio [OR] adjusted by sex=0.40, 95% confidence intervals [CI] 0.3, 0.6, p<0.001); rs7843014, OR=0.37, 95% CI 0.3, 0.5, p<0.001). The OR of being a centenarian if having the rs7460-TT genotype was 6.68 (95% CI 4.1, 10.8, p<0.001). The rs7843014 CC genotype was also positively associated with EL (OR=7.58, 95% CI 4.6, 12.3, p<0.001]. No association was, however, found for the Italian or Japanese cohorts. Thus, two genotypes of the FAK gene, rs7460 TT and rs7843014 CC, are possibly associated with lower gene expression and might favor the likelihood of reaching EL in the Spanish population. Further research is needed to unveil the mechanisms by which FAK expression could perhaps influence the rate of aging.

Editorial: Ageing, Longevity, Exceptional Longevity and Related Genetic and Non Genetics Markers: Panel Statement

In May 2012, a group of scientists and clinicians met in Athens (Greece) to consider the relevance of ageing, longevity, exceptional longevity and related genetic and non genetic markers. During this meeting, we firstly reviewed recent epidemiological and clinical studies on ageing, longevity and exceptional longevity, briefly analyzed the ageing theories and discussed successful and unsuccessful ageing also taking into account the evolutionary perspective. Secondly, we considered the three phenotypes based on the definition of ageing, longevity and exceptional longevity and the associated biomarkers. Third, we discussed proposed treatments suitable to counteract or slow down ageing. Finally, this panel produced a consensus statement to highlight the importance of ageing, longevity and exceptional longevity, since this is a rapidly increasing phenotype worldwide. We acknowledge that not all experts in this field may completely agree with this statement.

Becoming centenarians: disease and functioning trajectories of older US Adults as they survive to 100.

Little is known about the health and functioning of individuals who become centenarians in the years prior to reaching age 100. We examined long-term trajectories of disease, disability, and cognitive function in a sample of U.S. centenarians to determine how their aging experience differs from their nonsurviving cohort counterparts, and if there is heterogeneity in the aging experience of centenarians. Data are from the 1993-2010 waves of the nationally representative Health and Retirement Study. Among those who had the potential to become centenarians, we identified 1,045 respondents who died before reaching age 100 and 96 who survived to their 100th birthday. Respondents, or their proxies, reported on diagnosis of six major diseases (hypertension, heart disease, lung disease, stroke, cancer, and diabetes), limitations in activities of daily living, and cognitive function. As they age to 100, centenarians are generally healthier than nonsurviving members of their cohort, and a number of individuals who become centenarians reach 100 with no self-reported diseases or functional impairments. About 23% of centenarians reached age 100 with no major chronic disease and approximately the same number had no disability (18%). Over half (55%) reached 100 without cognitive impairment. Disease and functioning trajectories of centenarians differ by sex, education, and marital status. While some centenarians have poor health and functioning upon reaching age 100, others are able to achieve exceptional longevity in relatively good health and without loss of functioning. This study underscores the importance of examining variation in the growing centenarian population.

Exome sequencing of three cases of familial exceptional longevity.

Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands ≥ 103 years and at least one sibling ≥ 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5–13) or within individual families (66–156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A,NRG1,RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.

China as a “Civilization-State”: A Historical and Comparative Interpretation

Thanks to the publication of Martin Jacques's When China Rules the World, the notion of China as a “civilization-state” has gained wide currency in China studies. This essay revisits his reading of Chinese civilization from a historical and comparative perspective. Historically, despite its exceptional longevity and continuity, Chinese civilization has gone through major changes, especially since China's entrance into the modern world. In fact, modern China, while consciously or unconsciously abolishing and retaining different aspects of its traditions, has embraced some basic components from Western modernity. Hence the transformation of China into a modern nation – first by Sun Yat-sen's ephemeral bourgeois revolution, and then by Mao Zedong's decisive socialist revolution. Contemporary China continues to be shaped by the interaction between the remaining fragments from Chinese traditions and global, mainly Western, forces. Comparatively, the Western dichotomy between tradition and modernity simply does not apply to China. In many ways China has been modern (by Western standard) since ancient times. For instance, a largely secular state, a meritocratic bureaucracy, a highly self-governed civil society, a written language accessible to both literati and laypeople, a stratification system based on achieved rather than ascribed status, a cohesive culture open to multiculturalism, the idea and practice of educational equality, etc., which are fundamental to the formation of Western modernity, have long existed in China. On the other hand, Chinese society, premodern or modern, distinguishes itself by its, among other things, Confucian values, family morality in particular. Indeed, even today, Confucian familism (in forms of paternalism, nepotism, groupism, personalism, communalism, authoritarianism, etc.) is crucial to the operation of China's power system, market economy, and everyday life. Therefore, as a function of its civilization, China is both similar to and dissimilar from the West. In defining China as a civilization-state or, more specifically, in identifying the role of Chinese civilization in contemporary China, we need to decipher Chinese civilization in both its continuity and discontinuity in Chinese history, and in both its similarities with and differences from its Western counterpart.

Association of exceptional parental longevity and physical function in aging.

Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevity-associated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited. The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance (p = 0.009) and gait speed (p = 0.002). Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.

Defining successful aging: a tangible or elusive concept?

Everyone wants to age successfully; however, the definition and criteria of successful aging remain vague for laypersons, researchers, and policymakers in spite of decades of research on the topic. This paper highlights work of scholars who made significant theoretical contributions to the topic. A thorough review and evaluation of the literature on successful aging was undertaken. Our review includes early gerontological definitions of successful aging and related concepts. Historical perspectives reach back to philosophical and religious texts, and more recent approaches have focused on both process- and outcome-oriented models of successful aging. We elaborate on Baltes and Baltes' theory of selective optimization with compensation [Baltes, P. B., & Baltes, M. M. (1990a). Psychological perspectives on successful aging: The model of selective optimization with compensation. In P. B. Baltes & M. M. Baltes (Eds.), Successful aging: Perspectives from the behavioral sciences (pp. 1-34). United Kingdom: Cambridge University Press], Kahana and Kahana's preventive and corrective proactivity model [Kahana, E., & Kahana, B. (1996). Conceptual and empirical advances in understanding aging well through proactive adaptation. In V. Bengtson (Ed.), Adulthood and aging: Research on continuities and discontinuities (pp. 18-40). New York: Springer], and Rowe and Kahn's model of successful aging [Rowe, J. W., & Kahn, R. L. (1998). Successful aging. New York: Pantheon Books], outlining their commonalities and differences. Additional views on successful aging emphasize subjective versus objective perceptions of successful aging and relate successful aging to studies on healthy and exceptional longevity. Additional theoretical work is needed to better understand successful aging, including the way it can encompass disability and death and dying. The extent of rapid social and technological change influencing views on successful aging also deserves more consideration.

Exceptional longevity and exceptionally high metabolic rates in anthropoid primates are linked to a major modification of the ubiquinone reduction site of cytochrome b.

The maximal lifespan of Anthropoid primates (monkeys, apes and humans) exceed the lifespan of most other mammals of equal body mass. Unexpectedly, their exceptional longevity is associated with exceptionally high metabolic rates, in apparent contradiction to the Free Radical Theory of Aging. It was therefore suggested that in anthropoid primates (and several other taxa of mammals and birds) the mitochondrial electron transport complexes evolved to modify the relationship between basal electron transport and superoxide generation to allow for the evolution of exceptional longevity. Cytochrome b, the core protein of the bc1 complex is a major source of superoxide. The amino-acid sequence of cytochrome b evolved much faster in anthropoid than in prosimian primates, and most other mammals, resulting in a large change in the amino-acids composition of the protein. As a result of these changes cytochrome b in anthropoid primates is significantly less hydrophobic and contains more polar residues than other primates and most other mammals. Most of these changes are clustered around the reduction site of uboiquinone. In particular a key positively charged residue, arginine 313, that interacts with propionate D of heme bH, and thus raises its redox potential, is substituted in anthropoid primates with the neutral residue glutamine, most likely resulting in a lower redox potential of heme bH and faster reduction of ubiquinone at high proton motive force. It is suggested that these changes contribute to the observed increased rates of basal metabolism and reduce the rates of superoxide production, thus allowing for increased lifespan.

Serum Irisin Levels, Precocious Myocardial Infarction, and Healthy Exceptional Longevity

BackgroundSkeletal muscles produce irisin. Growing controversy exists on the association between this myokine and chronic disease risk. On the basis of the potential protective effects that irisin could exert on both vascular function and skeletal muscle mass, we hypothesized that an elevated level of this molecule may contribute to successful aging. MethodsSerum irisin levels were measured using enzyme-linked immunosorbent assay in disease-free centenarians, young healthy controls, and patients with precocious acute myocardial infarction. ResultsWe found the highest levels of serum irisin in disease-free centenarians (35.3 ± 5.5 ng/mL) compared with young healthy controls (20.7 ± 6.3 ng/mL) and especially with young patients with acute myocardial infarction (15.1 ± 5.4 ng/mL). ConclusionsOur study demonstrates that healthy centenarians are characterized by increased serum irisin levels, whereas levels of this molecule were found to be significantly lower in young patients with myocardial infarction. Our findings may prompt further research into the role played by irisin not only in vascular disorders but also in life span modulation.

FOXO3 and related transcription factors in development, aging, and exceptional longevity.

In June 2013, a workshop was convened in San Francisco to explore, in depth, the role of the Forkhead transcription factor FOXO3 (and related FOXOs) in development, aging, and, in particular, exceptional longevity. The presentations covered results derived from model systems, computational analysis and bioinformatics, and genomics and genome-wide association studies of a number of cohorts. Although the data collectively strongly reinforce FOXO3 and the FOXO/FOXO3 pathway as very important determinants in aging and life span, much of the detail of how the latter is achieved still remains unknown, in part, because of the very large number of genes (~2,200 in Caenorhabditis elegans) the transcription factor is involved in helping regulate. Particularly challenging at the present time is understanding the association of apparently nonfunctional specific variants (single nucleotide polymorphisms) of FOXO3 and exceptional longevity in humans, a finding replicated in a number of studies. Nonetheless, as summarized in this report, valuable information and insights were presented at the workshop on the transcription factor including but not limited to its role in determining longevity in C elegans and Drosophila (in flies, eg, an important interaction in aging occurs between dFOXO and the transforming growth factor-β/activin pathway), stem cell function and aging (notably in hematopoiesis), downstream regulatory activity (eg, by binding near sites of RNAse occupancy and altering chromatin structure), and as a potential target for the development a healthy aging drug (in this example, using compounds developed and screened to effect FOXO function in cancer cells).

“IDEAL” Aging Is Associated with Lower Resting Metabolic Rate: The Baltimore Longitudinal Study of Aging

To assess the associations among age, health status, and resting metabolic rate (RMR) in a large population of older adults. Cross-sectional analysis. Community-dwelling volunteers from the Baltimore Longitudinal Study of Aging (BLSA). Persons aged 40 to 96 (mean 68.2 ± 11.0) who underwent a comprehensive physical examination, cognitive assessment, RMR testing, body composition assessment, and physical function testing during a 3-day clinic visit (N = 420). Participants were assigned to Insight into the Determination of Exceptional Aging and Longevity (IDEAL) or non-IDEAL categories based on health status. IDEAL participants were defined according to the absence of physical and cognitive impairments, chronic conditions and comorbidities, and blood profile abnormalities. A three-stage linear regression model was used to assess the relationship between RMR and age, using IDEAL classification as a predictor and adjusting for sex and body composition. Resting metabolic rate averaged 1,512.4 ± 442.9 kcal/d and was lower with older age (β = -8.55, P < .001). After adjusting for age, sex, and body composition, RMR was 109.6 kcal/d lower in IDEAL than non-IDEAL participants (P < .005). Individuals who are fully functional and free of major medical conditions have lower RMR than those with disease and functional impairments. These findings suggest that health status plays a role in energy use and regulation independent of age and body composition and that elevated RMR may be a global biomarker of poor health in older persons.

Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity.

Attenuated growth hormone and insulin-like growth factor-1 (GH/IGF-1) signaling is associated with extended lifespan in several animal models. However, the effect of diminished GH/IGF-1 activity on survival in humans has not been confirmed. We tested the hypothesis that IGF-1 levels in nonagenarians (n = 184), measured at study enrollment, predict the duration of their incremental survival. In the Kaplan–Meier analysis, females with IGF-1 levels below the median (≤ 96 ng mL−1) had significantly longer survival compared with females with levels above the median, P < 0.01. However, this survival advantage was not observed in males (P = 0.83). On the other hand, in both males and females with a history of cancer, lower IGF-1 levels predicted longer survival (P < 0.01). IGF-1 level remained a significant predictor of survival duration in linear regression models after multivariable adjustment in females (P = 0.01) and individuals with a history of cancer (P < 0.01). We show for the first time that low IGF-1 levels predict life expectancy in exceptionally long-lived individuals.