Determinants Of Longevity Research Articles

Long‐lived yeast as a model for ageing research

Yeast has essentially two lifespans: a replicative lifespan (the number of daughters produced by each dividing mother cell) and a chronological lifespan (the capacity of stationary (G0) cultures to maintain viability over time). There is a tendency now to label every investigation that addresses these lifespans as ageing research. It is, though, analyses of the longest lifespans that will be most informative about the determinants of longevity and yield results most relevant to ageing in more complex systems. This review addresses these issues and describes the ongoing studies that are now attempting to address ageing in yeast cells of maximal replicative or chronological longevity.

P38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegans

The PMK-1 p38 mitogen-activated protein kinase pathway and the DAF-2–DAF-16 insulin signaling pathway control Caenorhabditis elegans intestinal innate immunity. pmk-1 loss-of-function mutants have enhanced sensitivity to pathogens, while daf-2 loss-of-function mutants have enhanced resistance to pathogens that requires upregulation of the DAF-16 transcription factor. We used genetic analysis to show that the pathogen resistance of daf-2 mutants also requires PMK-1. However, genome-wide microarray analysis indicated that there was essentially no overlap between genes positively regulated by PMK-1 and DAF-16, suggesting that they form parallel pathways to promote immunity. We found that PMK-1 controls expression of candidate secreted antimicrobials, including C-type lectins, ShK toxins, and CUB-like genes. Microarray analysis demonstrated that 25% of PMK-1 positively regulated genes are induced by Pseudomonas aeruginosa infection. Using quantitative PCR, we showed that PMK-1 regulates both basal and infection-induced expression of pathogen response genes, while DAF-16 does not. Finally, we used genetic analysis to show that PMK-1 contributes to the enhanced longevity of daf-2 mutants. We propose that the PMK-1 pathway is a specific, indispensable immunity pathway that mediates expression of secreted immune response genes, while the DAF-2–DAF-16 pathway appears to regulate immunity as part of a more general stress response. The contribution of the PMK-1 pathway to the enhanced lifespan of daf-2 mutants suggests that innate immunity is an important determinant of longevity.

Effects of Aging and Anti-Aging Caloric Restrictions on Carbonyl and Heat Shock Protein Levels and Expression

Heat shock proteins (Hsps) are induced by stressful stimuli and have been shown to protect cells and organs from such stresses both in vitro and in vivo, and play a positive role in lifespan determination. An attenuated response to stress is characteristic of senescence and no Hsp induction is observed upon exposure to stress and no protective effect of a mild stress is observed in cells from aged individuals. The artificial over-expression of Hsps, can produce a protective effect against a variety of damaging stimuli in cells from aged rats or aged humans, in whom cardiovascular disease is a major cause of morbidity in older age. Here, we show that aging significantly decreases the levels of Hsp27, Hsp60, Hsp72 and Hsc70 in right atrium and left ventricle of the rat heart, both at level of protein and of mRNA. Two different caloric restriction regimens have been found to counteract in part the decrease in the levels of Hsp expression in the aged heart tissue as well as the tendency to an increase of the levels of carbonyl in cardiac proteins. Our data suggest that cardiac Hsp levels may be a determinant of longevity in rodents, and that generation of new regimens of caloric restriction may eventually show how to improve modulation of cardiac aging.

Determinants of Mortality at Older Ages: The Role of Biological Markers of Chronic Disease

THE STUDY of mortality determinants has a long history in social science. Much of the early literature examined factors associated with mortality by estimating life tables for specific classifications of the population. These comparisons yielded insights on the relationship of mortality to age, sex, smoking habits, and socioeconomic variables, but they were less useful in revealing the simultaneous influence of multiple factors or the effect of measures beyond the classic socio-demographic variables in the demographer's toolkit. During the past few decades, the availability of micro-level data-especially from demographic and health interview surveys-and the concomitant use of multivariate models have permitted in-depth studies of the determinants of longevity (Elo and Preston 1996; Hayward and Gorman 2004). The resulting analyses have provided a better understanding of the complex mechanisms that mediate mortality risk. In particular, there is now a substantial literature investigating the salience of various self-reported dimensions of health for adult and old-age mortality (Hurd, McFadden, and

Longevity Determinant Genes: What is the Evidence? What's the Importance? Panel Discussion

Annals of the New York Academy of SciencesVolume 1055, Issue 1 p. 58-63 Longevity Determinant Genes: What is the Evidence? What's the Importance? Panel Discussion RICHARD CUTLER, RICHARD CUTLER ModeratorSearch for more papers by this authorL P GUARANTE, L P GUARANTESearch for more papers by this authorTHOMAS W. KENSLER, THOMAS W. KENSLERSearch for more papers by this authorFRED NAFTOLIN, FRED NAFTOLINSearch for more papers by this authorDEAN P. JONES, DEAN P. JONESSearch for more papers by this authorCHARLES R. CANTOR, CHARLES R. CANTORSearch for more papers by this authorGEORGE M. MARTIN, GEORGE M. MARTIN PanelistsSearch for more papers by this author RICHARD CUTLER, RICHARD CUTLER ModeratorSearch for more papers by this authorL P GUARANTE, L P GUARANTESearch for more papers by this authorTHOMAS W. KENSLER, THOMAS W. KENSLERSearch for more papers by this authorFRED NAFTOLIN, FRED NAFTOLINSearch for more papers by this authorDEAN P. JONES, DEAN P. JONESSearch for more papers by this authorCHARLES R. CANTOR, CHARLES R. CANTORSearch for more papers by this authorGEORGE M. MARTIN, GEORGE M. MARTIN PanelistsSearch for more papers by this author First published: 22 January 2006 https://doi.org/10.1196/annals.1323.010Citations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume1055, Issue1Longevity Health Sciences: The Phoenix ConferenceDecember 2005Pages 58-63 RelatedInformation

Scientific aspects of ageing: a lordly report

Scientific aspects of ageing: a lordly report

Chaperones and Longevity

That evolution of longevity may depend on alterations in the expression of relatively few regulatory genes has been inferred from the rapid increase in lifespan during evolution of the hominid species (Cutler RG (1979) Mech Ageing Dev 9: 337-354). Also the inherent immortality of the embryonic stem cells implies that replicative senescence (Hayflick L (1997) Biochem Mosc 62: 1180-1190) as possibly aging of species are epigenetic phenomena. Evidence is presented to suggest that the epigenetic changes of the longevity determinants to a significant extend concerns the molecular chaperones. Specific involvement of RNA chaperones in cell immortalization and defective RecQ-DNA chaperones in syndromes of premature aging suggest that DNA/RNA - chaperones probably rank high among the determinants of cellular and species longevity.

Risky business: explaining the gender gap in longevity

Background Women outlive men in all but the poorest and most unequal of countries, despite recent increases in male life expectancy that have exceeded those amongst women. This study identifies sources of disparity in longevity between sexes. Methods Canadian data on age and cause of all deaths recorded in 1999 are grouped and analyzed to identify sex differences in mortality. Results The overall ratio of male to female deaths (1.09 to 1) varies across ages, from a maximum of 2.6 male for every 1 female death between ages 15 and 29 years, to a minimum of 0.80 to 1 amongst those over 74 years old. The source of greatest disadvantage for men under age 45 years is behaviours attributable to gender. Accidents, injuries, and suicides account for the majority of the male mortality excess in this group, and for more male than female deaths amongst all but the most elderly. Before age 60 years, risk-taking behaviour claims more male lives than does circulatory disease. Conclusions Data presented show the significance of gender as a determinant of longevity, and suggest the value of interventions to ameliorate this effect.

RhoA, Rho kinase, JAK2, and STAT3 may be the intracellular determinants of longevity implicated in the progeric influence of obesity: Insulin, IGF-1, and leptin may all conspire to promote stem cell exhaustion

The aging process in higher mammals is increasingly being shown to feature a potentially substantial contribution from the longitudinal deterioration of normative stem cell dynamics seen with the passage of time. The precise mechanistic sequence producing this phenomenon is not entirely understood, but recent evidence has strongly implicated intracellular downstream effectors of endocrinologic pathways thought to be engaged by the obese state, specifically the insulin, IGF-1, and leptin signaling pathways. Among the intracellular effectors of these signals, a uniquely potent influence on stem cell dynamics may be attributable to Rho/ROCK, JAK kinase activity and STAT3 activity. In particular, it has already been shown that specific tyrosine kinase activities, such as that seen with Rho kinase, are presently thought to be associated with adverse health outcomes in numerous clinical contexts. Furthermore, the Rho GTPase is thought to be contributing to end-stage renal disease. However, in addition to its contribution to organ system dysfunction, the Rho/ROCK pathway has recently been shown to be activated by insulin and IGF-1, providing a tantalizing connection to nutrition and aging science. The JAK-STAT pathway, in contrast, has long been associated with pro-inflammatory cytokines, but has recently been implicated in leptin signaling as well. Importantly, JAK-STAT signaling has, similarly to Rho/ROCK signaling, been implicated as capable of accelerating stem cell proliferation. The implications of these recent determinations, in light of the recent finding of telomere attrition in humans associated with obesity, are that the intracellular determinants of aging may already be known, and the known common influence of these signaling elements on longitudinal stem cell dynamics is a pronounced induction of proliferation, an elevation that has been linked to the pathologic evolution of longitudinal organ-level dysfunction and the organismal-level physiologic decline seen with the inexorable passage of time. Besides the obvious utility for the management for human age-related dysfunction that investigation of pharmacologic inhibitors of these proteins would provide, interventions such as caloric restriction and possibly intermittent fasting may beneficially influence stem cell proliferation dynamics and reduce intracellular correlates of mitogenic drive. Integrating the findings present in the present body of research may reveal endocrinological states that are compatible with longevity, and will also provide novel insight into the specific proteomic determinants of age-related physiologic decline, ushering in a new epoch of medicine that fosters the management of the "pre-etiopathology" of chronic disease and disability of aging, therefore mitigating the suffering widely thought to be inherent in the latter stages of life.

Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

Computer Assisted Navigation in Total Knee Arthroplasty: Comparison With Conventional Methods

The success of knee arthroplasty is dependent on many factors. Postoperative extremity and component alignment are important determinants of outcome and longevity. Malalignment (>3°) results in higher failure rates. Computer-assisted navigation devices were developed to improve implant positioning. This study evaluated the early outcomes of a high-volume fellowship-trained surgeon relative to component positioning and limb alignment using an image-free navigation system. The navigation group consisted of 116 consecutive patients, and the conventional group consisted of 51 consecutive patients. The postoperative mechanical axis was within 3° of neutral mechanical alignment in 95% of the navigation cases vs 84% of the conventional cases ( P < .02). The range of the alignment and component position measurements narrowed, and the undesired outliers decreased. Accuracy was improved with navigation. Navigation was a viable device to improve the outcome of total knee arthroplasty relative to limb and component alignment.

Oxidative Stress and Aging: Catalase Is a Longevity Determinant Enzyme

Schriner and colleagues have reported an important advance in our understanding of the mechanisms controlling lifespan in mammalian species. A transgenic mouse strain was constructed (MCAT) with a C57BL/6J background that has about a 50-fold increase in expression in cardiac mitochondria and skeletal muscle of catalase enzyme activity. The MCAT strain was found to have reduced severity of age-dependent arteriosclerosis and increased genomic stability, as indicated by a decrease in oxidative stress and mitochondrial deletions in heart and muscle tissues. Most exciting, however, is that both median and maximum lifespan were increased about 17-21% compared to wild-type controls. It was disappointing that the Gompertz plot of the MCAT strain ran parallel to the wild-type control, indicating a delay in the onset of aging rather than a decrease in aging rate. Nevertheless, these results support the notion of a role for mitochondrial oxidative stress as a determinant of both healthspan and lifespan. In addition, the relatively large increase in lifespan resulting from upregulation of a single gene suggests the possibility that similar upregulation of relatively few key longevity determinant genes may result in dramatic increases in lifespan.

Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination

The IGF-1R is a genetic determinant of oxidative stress and longevity. Hyperglycemia induces an exponential increase in the production of a key danger signal, reactive oxygen intermediates, which target genomic DNA. Here, we report for the first time that ligand activation of the IGF-1R prevents hyperglycemia-induced genotoxic stress and enhances DNA repair, maintaining genomic integrity and cell viability. We performed single gel electrophoresis (comet assay) to evaluate DNA damage in serum-starved SV40 murine mesangial cells (MMC) and normal human mesangial cells (NHMC), maintained at high ambient glucose concentration. Hyperglycemia inflicted an impressive array of DNA damage in the form of single-strand breaks (SSBs) and double-strand breaks (DSBs). The inclusion of IGF-1 to culture media of MMC and NHMC prevented hyperglycemia-induced DNA damage. To determine whether DNA damage was mediated by reactive oxygen species (ROS), ROS generation was evaluated, in the presence of IGF-1, or the free radical scavenger n-acetyl-cysteine (NAC). IGF-1 and NAC inhibited hyperglycemic-induced ROS production and hyperglycemia-induced DNA damage. We next asked whether IGF-1 promotes the repair of DSB under hyperglycemic conditions, by homologous recombination (HRR) or nonhomologous end joining (NHEJ). Repair of DSB by NHEJ and HRR was operative in MMC maintained under hyperglycemic conditions. IGF-1 increased HRR by nearly twofold, whereas IGF-1 did not affect DNA repair by NHEJ. IGF-1R enhancement of HRR correlated with the translocation of Rad51 to foci of DNA damage. Inhibition of Rad51 expression by short interfering RNA experiments markedly decreased percentage of MMC positive for Rad51 nuclear foci and increased hyperglycemic DNA damage. We conclude that the activated IGF-1R rescues mesangial cells from hyperglycemia-induced danger signals that target genomic DNA by suppressing ROS and enhancing DNA repair by HRR.

The patterns and determinants of longevity in Russia's regions: Evidence from panel data

In this paper we examine whether regions of Russia have been converging or diverging in their longevity levels during the 1990s and evaluate the divergence effect of the 1998 financial crisis. We also estimate the impact of changes in poverty and public health spending on inter-temporal variations in longevity using regional-level panel data for 77 Russian regions from 1994 to 2000. Finally, we investigate the extent to which the gradual recovery in longevity observed after 1994 was derailed by the 1998 financial crisis and the public policy shifts required for regions to regain their Soviet-era levels of longevity. We find a significant negative effect of the 1998 crisis on longevity independently of the factors related directly to poverty and public health spending. In addition, a permanent negative shock to the incidence of poverty and the amount of publicly-provided health care in a region has enduring consequences on the population's health. Finally, the effect of increases in public health spending on longevity is related positively to the incidence of poverty. Journal of Comparative Economics 33 (4) (2005) 788–813.

Oversizing pulmonary homograft conduits does not significantly decrease allograft failure in children

Placement of oversized pulmonary ventricle-pulmonary artery conduits is routinely performed to decrease conduit failure in children. However, this practice has recently been challenged as somatic outgrowth may not be the main determinant of allograft failure in children. Our objective was to determine whether placement of oversized homografts for extracardiac pulmonary ventricle (PV) outflow tract reconstruction improves longevity in young children. We reviewed 102 consecutive PV-PA conduits inserted in 70 patients less than 18 years between 1984 and 2003. Conduits placed in an anatomic position (n=23) as part of a Ross operation, were excluded. Conduits were initially stratified into two age groups: Group 1, those placed in patients <or=10 years, and Group 2, those placed in patients >10 years. Normalization of conduit size to patient's body surface area at the time of insertion (z-value) was then performed to divide the conduits into oversized (O/S) and non-oversized (NO/S) groups. Determinants of conduit failure and allograft longevity were then compared between groups. Seventy-nine extracardiac conduits were placed, and 57 of these were in patients under 10 years of age. The majority had a diagnosis of tetralogy of Fallot (n=38), truncus arteriosus (n=19), pulmonary atresia with ventricular septal defect (n=12), or D-TGA with pulmonary stenosis and ventricular septal defect (n=7). Thirty-seven conduits were oversized (O/S) based on z-value, and 42 were non-oversized (NO/S), and the mean age at initial homograft placement was 7.0+/-7.5 years. Overall, oversizing conferred no significant advantage with respect to actuarial freedom from homograft replacement at 1, 5, or 10 years (96, 79, and 21%, O/S vs 93, 60, and 24%, NO/S), P=0.44. Oversizing was more frequent in Group 1 than Group 2 (53 vs 32%), and conduit failure was also more frequent with 49% requiring reoperation during the study period vs 38% in Group 2. In the subset of patients <or=10 years, both homograft explantation rate (50% O/S vs 48% NO/S) and median interval to conduit failure were similar between the O/S and NO/S patients (7.1 vs 4.8 years), P=0.340. Risk factors for conduit failure identified in multivariable regression analysis included the presence of pulmonary artery branch stenosis, lack of previous definitive repair, a diagnosis of pulmonary atresia, the need for percutaneous intervention. There is no significant benefit to placement of an oversized PV-PA homograft in this series of patients from a single institution. Even in young patients with rapid somatic growth, normalizing extracardiac allografts to BSA provides excellent conduit longevity and outcomes.

Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity

Immunosenescence is the consequence of the continuous attrition caused by chronic antigenic stress. The most important characteristics of immunosenescence (accumulation of memory and effector T cells, reduction of naive T cells, shrinkage of T cell repertoire, reduction of the immunological space) are compatible with this assumption. Immunosenescence can be taken as proof that the beneficial effects of the immune system, devoted to the neutralization of harmful agents early in life, become detrimental late in life, in a period not foreseen by evolution. This perspective could explain the mechanisms of the ageing process as well as the pathogenesis of age-related diseases.

Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: The cardiovascular health study

Inflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 −174 G/C, β-fibrinogen −455 G/A, plasminogen activator inhibitor (PAI)-1 −675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) −438 G/A in 2224 men and women ≥65 years old at baseline. During 10 years of follow-up, men with the TAFI −438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the −438 G allele. The effects of TAFI −438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 −174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.

Genetics of Longevity and Aging

Longevity, i.e., the property of being long-lived, has its natural limitation in the aging process. Longevity has a strong genetic component, as has become apparent from studies with a variety of organisms, from yeast to humans. Genetic screening efforts with invertebrates have unraveled multiple genetic pathways that suggest longevity is promoted through the manipulation of metabolism and the resistance to oxidative stress. To some extent, these same mechanisms appear to act in mammals also, despite considerable divergence during evolution. Thus far, evidence from population-based studies with humans suggests the importance of genes involved in cardiovascular disease as important determinants of longevity. The challenge is to test if the candidate longevity genes that have emerged from studies with model organisms exhibit genetic variation for life span in human populations. Future investigations are likely to involve large-scale case-control studies, in which large numbers of genes, corresponding to entire gene functional modules, will be assessed for all possible sequence variation and associated with detailed phenotypic information on each individual over extended periods of time. This should eventually unravel the genetic factors that contribute to each particular aging phenotype.

Bomb radiocarbon and lead - radium disequilibria in otoliths of bocaccio rockfish (Sebastes paucispinis): a determination of age and longevity for a difficult-to-age fish

Longevity estimates for the bocaccio rockfish (Sebastes paucispinis) using traditional techniques range from less than 20 years to approximately 50 years. Otoliths of bocaccio are difficult to age, and previous attempts to validate ages have been unsuccessful. Because otolith age suggests the bocaccio are reasonably long-lived, lead–radium dating was used in an attempt to independently age bocaccio otoliths. The measured 210Pb and 226Ra activities were among the lowest reported and resulted in poor radiometric age resolution; however, the break-and-burn technique clearly underestimated age in some cases with the longevity of the bocaccio being at least 31 years. To provide better age resolution, the bomb radiocarbon approach was applied to individual otoliths. Based on measured radiocarbon levels relative to a reference time-series, several specimens were aged at approximately 30–40 years. To evaluate these determinations, the remaining otolith of the pair was sectioned and aged blind. The result was an excellent fit to the reference time-series and a validation of the age estimates. The maximum age from growth zone counts was 37 ± 2 years, which is consistent with a reported maximum age of approximately 50 years.

Comparative Effects of Non-Gelatinized Corn and Rice Starches on the Life-Span of ICR Mice

We compared the effects of non-gelatinized rice and corn starches on the life-span of ICR mice. Six groups of male ICR mice consisting of 30 animals each were maintained on purified experimental diets containing either corn or rice starch and different amounts of soybean oil (6, 12 or 24%) throughout their life-time. Plots of the survival rates of the mice indicate that rice compared to corn starch conferred a longer life-span to ICR mice, although a significant difference due to the starch type was only observed in the mice fed on the 24% fat diet (p=0.012). A divergent effect of rice and corn starches on the survival rate was apparent when observations were combined with respect to the starch type regardless of the dietary fat level (p=0.005). In addition, two-way ANOVA data indicate that the mean survival time was longer for the mice given rice starch (593-645 days) than for those fed corn starch (538-580 days) (p=0.011). However, no significant difference in these parameters due to dietary fat levels was observed. The results of our study indicate that starch type is one of the determinants of longevity in mice.