Genetics of healthy aging and longevity

Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may ‘buffer’ the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.     

Genetic alteration of normal aging processes is responsible for extended longevity in Drosophila

The first step in a genetic analysis of aging is to identify and characterize the genetic mutants and their controls that will be used. Such mutants or strains are initially identified by their effect on the life span. Yet many genetic interventions are known to have some effect on the life span without necessarily affecting the aging process. It is therefore necessary to prove that one is actually dealing with an aging mutant before one draws strong inferences from the data. Casarett's rules provide an operational test for doing so, relying as they do on the comparison of aging bio-markers in the experimental and reference strains. We show that our previously described genetically based long-lived NDC-L strain and its normal-lived NDC-R control strain differ only in the chronological age of expression of two behavioral and three physiological functional age biomarkers. They do not differ in the sequence or the physiological age of expression of these biomarkers. These two strains comply with the Casarett rules and thereby comprise a valid tool with which to conduct a comparative genetic analysis of aging. The implications of the available data are discussed, including the possibility that aging in these strains of Drosophila melanogaster may be the result of a multiphasic developmental process.     

Denitrification losses from a natural grassland in the Basque Country under organic and inorganic fertilization

Denitrification losses from a poorly drained clayey loamy soil under natural pasture were measured over a two-year period using the acetylene inhibition technique. Plots received two different applications of fertilizer as calcium ammonium nitrate or cow slurry (a total of 145–290 kg N ha^–1 in 1991 and 120–240 kg in 1992). In the first year, N losses in the mineral treatments were about 4 times greater than losses in the slurry treatments. In the second year losses in the slurry treatments increased in such a way that losses in the higher slurry application became similar to those for the two mineral treatments. Soil nitrate was the factor producing differences between treatments. In this way, N mineralization in periods between fertilizations coinciding with high soil water contents was responsible in the second year for the increase in N losses in the slurry treatments. Denitrification rates greater than 0.1 kg N ha^–1 day^–1 occurred at soil water contents > 33 % (air filled porosity < 26 %) and soil nitrate contents > 1 mg N kg^–1 dry soil. Spring and autumn were the seasons of highest risk of denitrification because of N fertilizations coinciding with periods of soil saturation with water. Winter losses were low, but this is a period when there is a risk of denitrification in wetter seasons, particularly for a slurry application management.     

Sexual dimorphism in healthy aging and mild cognitive impairment: a DTI study

Previous PET and MRI studies have indicated that the degree to which pathology translates into clinical symptoms is strongly dependent on sex with women more likely to express pathology as a diagnosis of AD, whereas men are more resistant to clinical symptoms in the face of the same degree of pathology. Here we use DTI to investigate the difference between male and female white matter tracts in healthy older participants (24 women, 16 men) and participants with mild cognitive impairment (21 women, 12 men). Differences between control and MCI participants were found in fractional anisotropy (FA), radial diffusion (DR), axial diffusion (DA) and mean diffusion (MD). A significant main effect of sex was also reported for FA, MD and DR indices, with male control and male MCI participants having significantly more microstructural damage than their female counterparts. There was no sex by diagnosis interaction. Male MCIs also had significantly less normalised grey matter (GM) volume than female MCIs. However, in terms of absolute brain volume, male controls had significantly more brain volume than female controls. Normalised GM and WM volumes were found to decrease significantly with age with no age by sex interaction. Overall, these data suggest that the same degree of cognitive impairment is associated with greater structural damage in men compared with women.     

Between votes and bullets. Conflicting ethnic identities in the Basque Country

With settlement of the Northern Irish conflict, the Basque Country hosts the most threatening nationalist conflict in the European Union. After the breakdown of the ceasefire late in 1999, a return of intensive and indiscriminate ETA violence has provoked a political and social crisis for Basque (and Spanish) society, and, according to all recent opinion polls, the issue of terrorism now ranks first among citizens' worries. This article focuses on the historical origins of the Basque conflict, its evolution during the Francoist dictatorship (1939–75), and the reasons for its continuity in the new political context of democracy. Special attention is paid to the attempt of kick-starting a peace process in 1998, comparison with the Northern Irish experience, and factors which contributed to the collapse of that attempt of peaceful accommodation. Finally, in the light of the most outstanding theoretical approaches towards the explanation of political violence in the Basque Country, several proposals for the necessary rethinking of this problem are presented.     

Study of FMR1 gene association with ovarian dysfunction in a sample from the Basque Country

Premature ovarian failure (POF) is defined as cessation of menses before the age of 40. The most significant single gene associated with POF is the Fragile X Mental Retardation 1 gene (FMR1). In the present work we screened women with fertility problems from the Basque Country in order to determine, whether in these women, FMR1 CGG repeat size in the intermediate and premutation range was associated with their pathology, and whether intermediate and premutation carriers had endocrine signs of diminished ovarian function, using the most established measure of ovarian reserve, the gonadotropin FSH. A patient sample of 41 women with ovarian insufficiency and a control sample of 32 women with no fertility problems from the Basque Country were examined. The patient sample was classified into three categories according to the results of the retrospective assessment of their ovarian function. In group 2 of patients, women with irregular cycles, reduced fecundity and FSH levels ≥ 10 IU/l, there is a significant increase in the number of intermediate and premutation FMR1 alleles (35–54 CGG repeats). In group 3 of patients, women with amenorrhea for at least four consecutive months and FSH levels ≥ 10 IU/l, a significant increase in the number of intermediate FMR1 alleles (35–54 CGG repeats) was found in patients compared with controls. In this group all the patients had a serum concentration > 40 IU/l. The results suggest that in the analysed Basque sample the FMR1 gene has a role in the aetiology of POF. However, elevated FSH levels are more related to the menstrual cycle pattern than to the CGG repeat size.     

The reliability theory of aging and longevity.

Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy. Reliability theory also predicts the late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as an inevitable consequence of redundancy exhaustion at extreme old ages. The theory explains why mortality rates increase exponentially with age (the Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems. It also explains why organisms "prefer" to die according to the Gompertz law, while technical devices usually fail according to the Weibull (power) law. Theoretical conditions are specified when organisms die according to the Weibull law: organisms should be relatively free of initial flaws and defects. The theory makes it possible to find a general failure law applicable to all adult and extreme old ages, where the Gompertz and the Weibull laws are just special cases of this more general failure law. The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age, and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels. Overall, reliability theory has an amazing predictive and explanatory power with a few, very general and realistic assumptions. Therefore, reliability theory seems to be a promising approach for developing a comprehensive theory of aging and longevity integrating mathematical methods with specific biological knowledge.     

Decomposition processes of Spartina maritima in a salt marsh of the Basque Country

Decomposition dynamics of aerial parts and root-rhizomes of Spartina maritima in a Basque Country salt marsh was studied, using litter bags placed on the soil surface and buried 10 cm below ground. Aerial parts of the plant in aboveground position showed higher breakdown rates than samples placed belowground. There was no significant difference found between aerial parts and root-rhizomes buried. Nitrogen and phosphorus followed different dynamics (seasonal changes and progressive losses) that may be a consequence of distinctive mineralization pathways. The low faunal richness and densities belowground reflect the unfavourable life conditions in such a situation and, to a certain extent, the lower decomposition rates of buried litter. Four mathematical expressions that fit the data are presented and discussed.     

Action of estrogens in the aging brain: Dementia and cognitive aging

Background

Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging.

Scope of review

Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk.

Major conclusions

Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings.

General significance

Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause.     

Genetic signatures of exceptional longevity in humans

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.     

Diet as a modulator of aging and longevity.

The interrelationships between diet and life span are reviewed, with emphasis on results obtained in studies with experimental animals. Ad libitum feeding throughout life does not promote maximal survival and food restriction increases mean life span. The possible importance of total energy, carbohydrate, and protein intake are considered, as well as the influence of mode of feeding. A number of mechanisms that might explain how nutrition affects life span are discussed, including disease pattern, free radicals, neuroendocrine system, and protein turnover. The significance of these findings in relation to the health and life span of human subjects is not known and deserves further exploration. However, they emphasize the importance of diet as a tool to help explore the biochemical and physiological basis for aging in animal models.     

Seasonal succession of tintinnids in the Nervion River estuary, Basque Country, Spain

The seasonal succession of tintinnids was examined in the outerpart of the Nervión River estuary. Sampling was carriedout at monthly intervals from March 2000 to March 2002. In thisperiod, 21 species, belonging to 12 genera, were recorded, amongwhich Tintinnopsis was the most abundant genus, contributingup to 86% of the total ciliate abundance. The maximum abundancewas recorded in summer, with 7.4 x 10³ individuals L^-1 in July2001, while the lowest value occurred in winter. A significantand positive correlation was found between temperature and tintinnidabundance. Most of the species showed a distinct seasonal occurrenceand on this basis five different groups were differentiated.Two main changes in the species composition were recorded, onein March–April and the second in October–November.In this paper, the seasonal dynamics and the spatial distribution,as well as remarks on the morphology and ecology, of the mostimportant tintinnid species in the estuary are given.     

Ancestral origins of the prion protein gene D178N mutation in the Basque Country

Fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD) are familial prion diseases with autosomal dominant inheritance of the D178N mutation. FFI has been reported in at least 27 pedigrees around the world. Twelve apparently unrelated FFI and fCJD pedigrees with the characteristic D178N mutation have been reported in the Prion Diseases Registry of the Basque Country since 1993. The high incidence of familial prion diseases in this region may reflect a unique ancestral origin of the chromosome carrying this mutation. In order to investigate this putative founder effect, we developed happy typing, a new approach to the happy mapping method, which consists of the physical isolation of large haploid genomic DNA fragments and their analysis by the Polymerase Chain Reaction in order to perform haplotypic analysis instead of pedigree analysis. Six novel microsatellite markers, located in a 150-kb genomic segment flanking the PRNP gene were characterized for typing haploid DNA fragments of 285 kb in size. A common haplotype was found in patients from the Basque region, strongly suggesting a founder effect. We propose that happy typing constitutes an efficient method for determining disease-associated haplotypes, since the analysis of a single affected individual per pedigree should provide sufficient evidence.     

Genetic model for longitudinal studies of aging, health, and longevity and its potential application to incomplete data

Many longitudinal studies of aging collect genetic information only for a sub-sample of participants of the study. These data also do not include recent findings, new ideas and methodological concepts developed by distinct groups of researchers. The formal statistical analyses of genetic data ignore this additional information and therefore cannot utilize the entire research potential of the data. In this paper, we present a stochastic model for studying such longitudinal data in joint analyses of genetic and non-genetic sub-samples. The model incorporates several major concepts of aging known to date and usually studied independently. These include age-specific physiological norms, allostasis and allostatic load, stochasticity, and decline in stress resistance and adaptive capacity with age. The approach allows for studying all these concepts in their mutual connection, even if respective mechanisms are not directly measured in data (which is typical for longitudinal data available to date). The model takes into account dependence of longitudinal indices and hazard rates on genetic markers and permits evaluation of all these characteristics for carriers of different alleles (genotypes) to address questions concerning genetic influence on aging-related characteristics. The method is based on extracting genetic information from the entire sample of longitudinal data consisting of genetic and non-genetic sub-samples. Thus it results in a substantial increase in the accuracy of statistical estimates of genetic parameters compared to methods that use only information from a genetic sub-sample. Such an increase is achieved without collecting additional genetic data. Simulation studies illustrate the increase in the accuracy in different scenarios for datasets structurally similar to the Framingham Heart Study. Possible applications of the model and its further generalizations are discussed.     

Profiles of random change during aging contain hidden information about longevity and the aging process.

Many different morphological and physiological changes occur during the yeast replicative lifespan. It has been proposed that change is a cause rather than an effect of aging. It is difficult to ascribe causality to processes that manifest themselves at the level of the entire organism, because of their global nature. Although causal connections can be established for processes that occur at the molecular level, their exact contributions are obscured, because they are immersed in a highly interactive network of processes. A top-down approach that can isolate crucial features of aging processes for further study may be a productive avenue. We have mathematically depicted the complicated and random changes that occur in cellular spatial organization during the lifespan of individual yeast cells. We call them budding profiles. This has allowed us to demonstrate that budding profiles are a highly individual characteristic, and that they are correlated with an individual cell's longevity. Additional information can be extracted from our model, indicating that random budding is associated with longevity. This expectation was confirmed, providing new avenues for exploring causal factors in yeast aging. The methodology described here can be readily applied to other aspects of aging in yeast and in higher organisms.     

Genetic coregulation of longevity and antioxienzymes in Neurospora crassa

Further analysis of a model of the biochemical genetics of cellular longevity in Neurospora crassa confirms and amplifies the hypothesis that antioxienzymes and lifespans are genetically co-regulated. The model consists of seven classes of closely related strains with genetically determined median lifespans ranging from 7 to 90 days and differing by about 15-day intervals. The nuclear gene mutations Age- and age+ respectively decrease and increase both lifespans and the constitutive enzyme activities relative to the wild-type parent. Here the number of such enzymes correlated with lifespans is extended from 6 to 12. Four of these enzymes have not been previously noted in Neurospora. Statistical analysis indicates that the genes may coordinate the 12 enzymes' activities with respect to one another to facilitate their "collaborative" function. The genes probably perform a regulatory role in the synthesis of the antioxienzymes. Neurospora may have a global unit of genetic function, an oxy-regulon, analogous to that of enteric bacteria.