Determinants Of Longevity Research Articles

RE: "INFLUENCE OF EXERCISE, WALKING, CYCLING, AND OVERALL NONEXERCISE PHYSICAL ACTIVITY ON MORTALITY IN CHINESE WOMEN"

This investigation described the effects of exercise, walking, and cycling for transportation, as well as the effect of overall nonexercise physical activity, on mortality in the Shanghai Women’s Health Study (1997–2004). Women without heart disease, stroke, or cancer were followed for an average of 5.7 years (n ¼ 67,143), and there were 1,091 deaths from all causes, 537 deaths from cancer, and 251 deaths from cardiovascular diseases. Information about physical activity and relevant covariates was obtained by interview. Proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals. Exercise and cycling for transportation were both inversely and independently associated with all-cause mortality (ptrend < 0.05), but walking for transportation was less strongly associated with reduced risk (ptrend ¼ 0.07). Women reporting no regular exercise but who reported 10 or more metabolic equivalent (MET)-hours/day of nonexercise activity were at 25–50% reduced risk (ptrend < 0.01) relative to less active women (0–9.9 MET-hours/day). Among women reporting the least nonexercise activity (0–9.9 MET-hours/day) but reporting regular exercise participation, exercise was associated with reduced mortality (hazard ratio ¼ 0.78, 95% confidence interval: 0.62, 0.99). These findings add new evidence that overall physical activity levels are an important determinant of longevity, and that health benefit can be obtained through an active lifestyle, exercise, or combinations of both. cardiovascular diseases; cohort studies; exercise; mortality; motor activity; neoplasms

Does Education Matter? Major League Baseball Players and Longevity

The authors used duration analysis to examine the longevity of Major League Baseball players. Using data on players who were born between 1945 and 1964, the authors found that the hazard rate of death for players who only attended high school was almost 2.0 times higher than those players who attended a 4-year university, evidence that the educaton–health link applies to professional athletes. Another important determinant of longevity was race. In addition, a player's body mass index was positively associated with a higher hazard of death. Compared with the general population, the death rate of baseball players was lower—the observed number of deaths in the dataset was only 31% of the expected number. Findings in this article are likely attributable to education being correlated with other variables that affect longevity, most likely intelligence and time preference.

Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins

Calorie restriction (CR) extends the mean and maximum lifespan of a wide variety of organisms ranging from yeast to mammals, although the molecular mechanisms of action remain unclear. For the budding yeast Saccharomyces cerevisiae reducing glucose in the growth medium extends both the replicative and chronological lifespans (CLS). The conserved NAD(+)-dependent histone deacetylase, Sir2p, promotes replicative longevity in S. cerevisiae by suppressing recombination within the ribosomal DNA locus and has been proposed to mediate the effects of CR on aging. In this study, we investigated the functional relationships of the yeast Sirtuins (Sir2p, Hst1p, Hst2p, Hst3p and Hst4p) with CLS and CR. SIR2, HST2, and HST4 were not major regulators of CLS and were not required for the lifespan extension caused by shifting the glucose concentration from 2 to 0.5% (CR). Deleting HST1 or HST3 moderately shortened CLS, but did not prevent CR from extending lifespan. CR therefore works through a Sirtuin-independent mechanism in the chronological aging system. We also show that low temperature or high osmolarity additively extends CLS when combined with CR, suggesting that these stresses and CR act through separate pathways. The CR effect on CLS was not specific to glucose. Restricting other simple sugars such as galactose or fructose also extended lifespan. Importantly, growth on nonfermentable carbon sources that force yeast to exclusively utilize respiration extended lifespan at nonrestricted concentrations and provided no additional benefit when restricted, suggesting that elevated respiration capacity is an important determinant of chronological longevity.

Analysis of HLA-DRB1,DQA1,DQB1 haplotypes in Sardinian centenarians

Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1∗15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a role in the association to diseases. Hence, we have evaluated, by amplification refractory mutation system/polymerase chain reaction (ARMS-PCR) the HLADQA1 and HLA-DQB1 allele frequencies in 123 centenarians and 92 controls from Sardinia to assess whether the association to HLA-DRB1∗15 allele may be due to the other genes involved in the HLA-DR,DQ haplotypes. The frequencies of HLA-DQA1,DQB1 haplotypes were not significantly modified in centenarians. Nevertheless by evaluating the frequency of DRB1∗15 linked haplotypes, we observed a not significant increase in centenarians of HLA-DQA1∗01,DQB1∗05 and HLA-DQA1∗01,DQB1∗06 haplotypes. These data suggest that these haplotypes might have a role in determining life span expectancy and longevity.

Apoptosis Remodeling in Immunosenescence: Implications for Strategies to Delay Ageing

Immunosenescence is characterized by a peculiar remodeling of the immune system, mainly induced by lifelong antigenic burden and oxidative stress. Apoptosis or programmed cell death plays a central role in the ageing process. Both recurrent antigenic stimulations and oxidative metabolism by-products, impinging upon the immune system, modify the apoptotic capability of lymphocytes, driving immunosenescence. The apoptosis remodeling, in addition to inflamm-ageing, i.e. the upregulation of anti-stress responses and inflammatory cytokines, represents one of the major determinants of ageing rate and longevity, as well as of the most common age-related diseases. The cells of the immune system undergo two different kinds of apoptotic processes: activation-induced cell death (AICD), geared towards the elimination of unnecessary lymphocytes following clonal expansion, and damage-induced cell death (DICD), particularly important for preventing the onset of neoplastic proliferations. During senescence these apoptotic pathways are differentially modulated, with variable impacts on the ageing process. A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degenerative, inflammatory and neoplastic diseases whose incidence increases with age. This review focuses on the role of AICD and DICD dysfunction in the ageing process and highlights emerging anti-ageing therapeutical strategies offered by apoptosis re-modulation. The challenge for the future is to identify factors and signals that regulate apoptotic processes and determine if selective apoptosis manipulation in specific lymphocyte subsets could preserve immune function in the elderly, contributing to successful ageing.

Biological Aging Is No Longer an Unsolved Problem

The belief that aging is still an unsolved problem in biology is no longer true. Of the two major classes of theories, the one class that is tenable is derivative of a single common denominator that results in only one fundamental theory of aging. In order to address this complex subject, it is necessary to first define the four phenomena that characterize the finitude of life. These phenomena are aging, the determinants of longevity, age-associated diseases, and death. There are only two fundamental ways in which age changes can occur. Aging occurs either as the result of a purposeful program driven by genes or by events that are not guided by a program but are stochastic or random, accidental events. The weight of evidence indicates that genes do not drive the aging process but the general loss of molecular fidelity does. Potential longevity is determined by the energetics of all molecules present at and after the time of reproductive maturation. Thus, every molecule, including those that compose the machinery involved in turnover, replacement, and repair, becomes the substrate that experiences the thermodynamic instability characteristic of the aging process. However, the determinants of the fidelity of all molecules produced before and after reproductive maturity are the determinants of longevity. This process is governed by the genome. Aging does not happen in a vacuum. Aging must be the result of changes that occur in molecules that have existed at one time with no age changes. It is the state of these pre-existing molecules that governs longevity determination. The distinction between the aging process and age-associated disease is not only based on the molecular definition of aging described above but it is also rooted in several practical observations. Unlike any disease, age changes (a) occur in every multicellular animal that reaches a fixed size at reproductive maturity, (b) cross virtually all species barriers, (c) occur in all members of a species only after the age of reproductive maturation, (d) occur in all animals removed from the wild and protected by humans even when that species probably has not experienced aging for thousands or even millions of years, (e) occur in virtually all animate and inanimate matter, and (f) have the same universal molecular etiology, that is, thermodynamic instability. Unlike aging, there is no disease or pathology that shares these six qualities. Because this critical distinction is poorly understood, there is a continuing belief that the resolution of age-associated diseases will advance our understanding of the fundamental aging process. It will not. The distinction between disease and aging is also critical for establishing science policy because although policy makers understand that the funding of research on age-associated diseases is an unquestioned good, they also must understand that the resolution of age-associated diseases will not provide insights into understanding the fundamental biology of age changes. They often believe that it will and base decisions on that misunderstanding. The impact has been to fund research on age-associated diseases at several orders of magnitude greater than what is available for research on the biology of aging. There is an almost universal belief by geriatricians and others that the greatest risk factor for all of the leading causes of death is old age. Why then are we not devoting significantly greater resources to understanding more about the greatest risk factor for every age-associated pathology by attempting to answer this fundamental question-"What changes occur in biomolecules that lead to the manifestations of aging at higher orders of complexity and then increase vulnerability to all age-associated pathology?"

Is superoxide dismutase a determinant of longevity in the nematode C. elegans?

Is superoxide dismutase a determinant of longevity in the nematode C. elegans?

Influence of Exercise, Walking, Cycling, and Overall Nonexercise Physical Activity on Mortality in Chinese Women

This investigation described the effects of exercise, walking, and cycling for transportation, as well as the effect of overall nonexercise physical activity, on mortality in the Shanghai Women's Health Study (1997-2004). Women without heart disease, stroke, or cancer were followed for an average of 5.7 years (n = 67,143), and there were 1,091 deaths from all causes, 537 deaths from cancer, and 251 deaths from cardiovascular diseases. Information about physical activity and relevant covariates was obtained by interview. Proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals. Exercise and cycling for transportation were both inversely and independently associated with all-cause mortality (p(trend) < 0.05), but walking for transportation was less strongly associated with reduced risk (p(trend) = 0.07). Women reporting no regular exercise but who reported 10 or more metabolic equivalent (MET)-hours/day of nonexercise activity were at 25-50% reduced risk (p(trend) < 0.01) relative to less active women (0-9.9 MET-hours/day). Among women reporting the least nonexercise activity (0-9.9 MET-hours/day) but reporting regular exercise participation, exercise was associated with reduced mortality (hazard ratio = 0.78, 95% confidence interval: 0.62, 0.99). These findings add new evidence that overall physical activity levels are an important determinant of longevity, and that health benefit can be obtained through an active lifestyle, exercise, or combinations of both.

Molecular Genetic Studies on Relationships among Longevity, Diseases, and HLA-DRB1/DQB1 Allelic Polymorphism

Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity reside in those polymorphisms for human leukocyte antigen (HLA) genes that have been involved in associations with many diseases (Caruso et al., 2001; Izaks et al., 2000). We are interested in understanding whether the HLA class II DRB1 /DQB1 allelic polymorphism is a common or independent factor both some diseases and longevity. Twenty subjects (12 men/8 women) nonagenarian aged 90 years or over from the northern Han Chinese living in Dalian were recruited as a longevity group. Disease groups consisted of patients with immune-associated diseases obviously affecting life span, including cirrhosis of liver, chronic renal failure, and solid tumor. About 20 subjects were selected randomly into each of the three disease groups, cirrhosis of liver, renal failure, and tumor, respectively. The control population was 81 healthy blood donors (41 men/40 women) from the same geographical area.

Cumulative Index of Elderly Disorders And Its Dynamic Contribution to Mortality And Longevity

The composite index constructed from longitudinal survey data as the level of deficits accumulated by an individual (frailty index) captures important systemic aspects of deterioration in a human organism, and is an attractive candidate for studying determinants of aging and longevity. The objective of this paper was to investigate the ability of this index to characterize human aging, mortality, and longevity. We use 32 variables from the National Long Term Care Survey data characterizing health and daily activities deficits to construct the cumulative frailty index. We use the Cox's proportional hazard model to describe its contribution to mortality. The risk of death considered as the function of the frailty index has asymmetric U-shaped form. The asymmetric U-function of the absolute risk is getting steeper (narrower) with age. The asymmetric U-function describing the relative risk exhibits the opposite tendency with age. The narrowing of the absolute risk functions with age reflects the age-related decline in stress resistance. The widening of the relative risk function with age indicates an increase in the relative contribution of other, unobserved, risk factors (including senescence) to the risk of death. This suggests increasing the role of senescence per se in the increasing risk of death with age compared to the role of specific pathology.

DEVELOPMENT OF QUALITY CONTROL PROCEDURES FOR MASS PRODUCED AND RELEASED BACTROCERA PHILIPPINENSIS (DIPTERA: TEPHRITIDAE) FOR STERILE INSECT TECHNIQUE PROGRAMS

Quality control procedures for Bactrocera philippinensis Drew & Hancock 1994 (Diptera: Tephritidae) used in sterile insect technique (SIT) programs were established in the mass rearing facility at the Philippine Nuclear Research Institute. Basic studies on pupal irradiation, holding/packaging systems, shipping procedures, longevity, sterility studies, and pupal eye color determination in relation to physiological development at different temperature regimes were investigated. These studies will provide baseline data for the development of quality control protocols for an expansion of B. philippinensis field programs with an SIT component in the future.

Entropy Explains Aging, Genetic Determinism Explains Longevity, and Undefined Terminology Explains Misunderstanding Both

Communication in the field of biogerontology is a minefield because all of the commonly used terms have no universally accepted definitions. In a series of five annual meetings that I chaired recently in an attempt to define common terms, the dozen or more experts who attended could not agree on the definition of almost all of them, including “aging.” The committee was disbanded and the communications dilemma remains. “Aging, Bench to Bedside,” the collection of mini reviews published as a series in this journal, is representative of this unsolved problem. Not only does the problem result in communication failures, it also produces erroneous interpretations of research results; illogical allocation of research funds; and misdirected scientific, economic, social, and political policy decisions [1–3]. There is no other field of science in which a similarly bleak situation exists. As a consequence of the terminology dilemma, I will define for use in this editorial the four aspects of the finitude of life: aging, the determinants of longevity, age-associated diseases, and death. I will not discuss the latter, although even this word defies a universally accepted definition.

Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study.

Centenarians represent a rare phenotype appearing in roughly 10-20 per 100,000 persons in most industrialized countries but as high as 40-50 per 100,000 persons in Okinawa, Japan. Siblings of centenarians in Okinawa have been found to have cumulative survival advantages such that female centenarian siblings have a 2.58-fold likelihood and male siblings a 5.43-fold likelihood (versus their birth cohorts) of reaching the age of 90years. This is indicative of a strong familial component to longevity. Centenarians may live such extraordinarily long lives in large part due to genetic variations that either affect the rate of aging and/or have genes that result in decreased susceptibility to age-associated diseases. Some of the most promising candidate genes appear to be those involved in regulatory pathways such as insulin signaling, immunoinflammatory response, stress resistance or cardiovascular function. Although gene variants with large beneficial effects have been suggested to exist, only APOE, an important regulator of lipoproteins has been consistently associated with a longer human lifespan across numerous populations. As longevity is a very complex trait, several issues challenge our ability to identify its genetic influences, such as control for environmental confounders across time, the lack of precise phenotypes of aging and longevity, statistical power, study design and availability of appropriate study populations. Genetic studies on the Okinawan population suggest that Okinawans are a genetically distinct group that has several characteristics of a founder population, including less genetic diversity, and clustering of specific gene variants, some of which may be related to longevity. Further work on this population and other genetic isolates would be of significant interest to the genetics of human longevity.

Determinants of longevity and all-cause mortality among middle-aged men. Role of 48 personal characteristics in a 40-year follow-up of Italian Rural Areas in the Seven Countries Study

Forty-year all-cause mortality and its association with entry risk factor levels are reported for men enrolled in the Italian Rural Areas of the Seven Countries Study of Cardiovascular Diseases. Forty-eight potential risk factors were measured in 1712 men aged 40-59 at entry examination in 1960. Mortality data were collected during 40 years of follow-up. The relationship of entry risk factor levels with all-cause mortality was studied by univariate and multivariate approaches. Overall death rate was 83.7%. The main causes of death were cardiovascular diseases, followed by cancer and others. The 48 risk factors were tested with univariate and multivariate approaches. In the final model, 15 risk factors were strongly and significantly related to all-cause mortality and survival. They were age, father and mother history of premature mortality, cigarette smoking, job-related physical activity (protective), body mass index (BMI) (in an inverse J-shaped fashion), mid-arm circumference (protective), mean blood pressure, forced respiratory volume in 3/4 seconds (protective), serum cholesterol, corneal arcus, xanthelasma, presence of cardiovascular diseases, cancer and diabetes at entry examination. During a 40-year period 15 mainly cardiovascular risk factors were highly predictive of all-cause mortality and survival in middle-aged men.

Oxidation-Resistant Membrane Phospholipids Can Explain Longevity Differences Among the Longest-Living Rodents and Similarly-Sized Mice

Underlying causes of species differences in maximum life span (MLS) are unknown, although differential vulnerability of membrane phospholipids to peroxidation is implicated. Membrane composition and longevity correlate with body size; membranes of longer-living, larger mammals have less polyunsaturated fatty acid (PUFA). We determined membrane phospholipid composition of naked mole-rats (MLS > 28.3 years) and similar-sized mice (MLS = 3-4 years) by gas-liquid chromatography to assess if the approximately 9x MLS difference could be explained. Mole-rat membrane composition was unchanged with age. Both species had similar amounts of membrane total unsaturated fatty acids; however, mice had 9 times more docosahexaenoic acid (DHA). Because this n-3PUFA is most susceptible to lipid peroxidation, mole-rat membranes are substantially more resistant to oxidative stress than are mice membranes. Naked mole-rat peroxidation indices, calculated from muscle and liver mitochondrial membranes, concur with those predicted by MLS rather than by body size, suggesting that membrane phospholipid composition is an important determinant of longevity.

Determinants of Longevity and Success in Lebanese Family Businesses: An Exploratory Study

This article explores the characteristics of Lebanese family businesses using a sample of 114 firms and tests various propositions regarding the relationships between correlates of effective succession planning and longevity. Successful family businesses in Lebanon exhibit a variety of responses to the variables that are conducive to success. The findings indicate that older firms are more inclined to use a participatory decision-making process, as evidenced by more reliance on advisory boards. A significantly larger proportion of older firms relative to younger ones holds family meetings and has formal redemption and liquidity plans. Firms in our sample are characterized by liberal attitudes: more than 75% consider female ownership acceptable and more than two-thirds of the firms respond positively to potential female CEOs.

White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study

High white matter grade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular size is a marker of brain “atrophy.” In the Cardiovascular Health Study (CHS) ( n = 3245) mean age 75 years, 50% black and 40% men, we evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting for numerous determinants of longevity over an approximate 10–12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5–6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals.

The quest for genetic determinants of human longevity: challenges and insights.

Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.

Identification of longevity-associated genes in long-lived Snell and Ames dwarf mice

Recent landmark molecular genetic studies have identified an evolutionarily conserved insulin/IGF-1 signal transduction pathway that regulates lifespan. In C. elegans, Drosophila, and rodents, attenuated insulin/IGF-1 signaling appears to regulate lifespan and enhance resistance to environmental stress. The Ames (Prop1 (df/df)) and Snell (Pit1 (dw/dw)) hypopituitary dwarf mice with growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin deficiencies live 40-60% longer than control mice. Both mutants are resistant to multiple forms of environmental stress in vitro. Taken collectively, these genetic models indicate that diminished insulin/IGF-l signaling may play a central role in the determination of mammalian lifespan by conferring resistance to exogenous and endogenous stressors. These pleiotropic endocrine pathways control diverse programs of gene expression that appear to orchestrate the development of a biological phenotype that promotes longevity. With the ability to investigate thousands of genes simultaneously, several microarray surveys have identified potential longevity assurance genes and provided information on the mechanism(s) by which the dwarf genotypes (dw/dw) and (df/df), and caloric restriction may lead to longevity. We propose that a comparison of specific changes in gene expression shared between Snell and Ames dwarf mice may provide a deeper understanding of the transcriptional mechanisms of longevity determination. Furthermore, we propose that a comparison of the physiological consequences of the Pit1dw and Prop1df mutations may reveal transcriptional profiles similar to those reported for the C. elegans and Drosophila mutants. In this study we have identified classes of genes whose expression is similarly affected in both Snell and Ames dwarf mice. Our comparative microarray data suggest that specific detoxification enzymes of the P(450) (CYP) family as well as oxidative and steroid metabolism may play a key role in longevity assurance of the Snell and Ames dwarf mouse mutants. We propose that the altered expression of these genes defines a biochemical phenotype which may promote longevity in Snell and Ames dwarf mice.

The nuclear hormone receptor DAF‐12 has opposing effects on Caenorhabditis elegans lifespan and regulates genes repressed in multiple long‐lived worms

The orphan nuclear hormone receptor gene daf-12 in Caenorhabditis elegans plays a key role in the regulation of development and determination of adult longevity. To understand the effects of daf-12 on aging we characterized the lifespan of loss-of-function and gain-of-function daf-12 alleles that have been identified on the basis of their effects on dauer development. We find that these mutations have opposing effects on longevity and resistance to oxidative and thermal stress which makes daf-12 the first gene with alleles that can extend or shorten lifespan. We find that the shortened lifespan of the loss-of-function mutation is due to accelerated aging in young adulthood rather than an adverse effect of the mutation on development. Microarray analysis of worms carrying the two alleles revealed a relatively small number of genes differentially expressed between the two genotypes. Comparison of the expression profiles with the profiles associated with dauer formation and long-lived daf-2 mutants revealed that while the profiles are largely different, there is significant overlap among the genes down-regulated, but not up-regulated, in all profiles. Several of these genes down-regulated in multiple long-lived worms have known effects on lifespan, and many of the genes belong to a family of poorly characterized genes that are strongly down-regulated in dauers, daf-2 mutants, and long-lived daf-12 mutants. Our results point to daf-12 modulating aging and stress responses in part through the repression of specific genes, and emphasize the role that the repression of genes that curtail maximal lifespan plays in lifespan determination.