Genes, ageing and longevity in humans: problems, advantages and perspectives

Many epidemiological data indicate the presence of a strong familial component of longevity that is largely determined by genetics, and a number of possible associations between longevity and allelic variants of genes have been described. A breakthrough strategy to get insight into the genetics of longevity is the study of centenarians, the best example of successful ageing. We review the main results regarding nuclear genes as well as the mitochondrial genome, focusing on the investigations performed on Italian centenarians, compared to those from other countries. These studies produced interesting results on many putative “longevity genes”. Nevertheless, many discrepancies are reported, likely due to the population-specific interactions between gene pools and environment. New approaches, including large-scale studies using high-throughput techniques, are urgently needed to overcome the limits of traditional association studies performed on a limited number of polymorphisms in order to make substantial progress to disentangle the genetics of a trait as complex as human longevity.     

Systems biology of ageing and longevity

Ageing is intrinsically complex, being driven by multiple causal mechanisms. Each mechanism tends to be partially supported by data indicating that it has a role in the overall cellular and molecular pathways underlying the ageing process. However, the magnitude of this role is usually modest. The systems biology approach combines (i) data-driven modelling, often using the large volumes of data generated by functional genomics technologies, and (ii) hypothesis-driven experimental studies to investigate causal pathways and identify their parameter values in an unusually quantitative manner, which enables the contributions of individual mechanisms and their interactions to be better understood, and allows for the design of experiments explicitly to test the complex predictions arising from such models. A clear example of the success of the systems biology approach in unravelling the complexity of ageing can be seen in recent studies on cell replicative senescence, revealing interactions between mitochondrial dysfunction, telomere erosion and DNA damage. An important challenge also exists in connecting the network of (random) damage-driven proximate mechanisms of ageing with the higher level (genetically specified) signalling pathways that influence longevity. This connection is informed by actions of natural selection on the determinants of ageing and longevity.     

Genes encoding longevity: from model organisms to humans

Ample evidence from model organisms has indicated that subtle variation in genes can dramatically influence lifespan. The key genes and molecular pathways that have been identified so far encode for metabolism, maintenance and repair mechanisms that minimize age-related accumulation of permanent damage. Here, we describe the evolutionary conserved genes that are involved in lifespan regulation of model organisms and humans, and explore the reasons of discrepancies that exist between the results found in the various species. In general, the accumulated data have revealed that when moving up the evolutionary ladder, together with an increase of genome complexity, the impact of candidate genes on lifespan becomes smaller. The presence of genetic networks makes it more likely to expect impact of variation in several interacting genes to affect lifespan in humans. Extrapolation of findings from experimental models to humans is further complicated as phenotypes are critically dependent on the setting in which genes are expressed, while laboratory conditions and modern environments are markedly dissimilar. Finally, currently used methodologies may have only little power and validity to reveal genetic variation in the population. In conclusion, although the study of model organisms has revealed potential candidate genetic mechanisms determining aging and lifespan, to what extent they explain variation in human populations is still uncertain.     

Tragedy and delight: the ethics of decelerated ageing

Biogerontology is sometimes viewed as similar to other forms of biomedical research in that it seeks to understand and treat a pathological process. Yet the prospect of treating ageing is extraordinary in terms of the profound changes to the human condition that would result. Recent advances in biogerontology allow a clearer view of the ethical issues and dilemmas that confront humanity with respect to treating ageing. For example, they imply that organismal senescence is a disease process with a broad spectrum of pathological consequences in late life (causing or exascerbating cardiovascular disease, cancer, neurodegenerative disease and many others). Moreover, in laboratory animals, it is possible to decelerate ageing, extend healthy adulthood and reduce the age-incidence of a broad spectrum of ageing-related diseases. This is accompanied by an overall extension of lifespan, sometimes of a large magnitude. Discussions of the ethics of treating ageing sometimes involve hand-wringing about detrimental consequences (e.g. to society) of marked life extension which, arguably, would be a form of enhancement technology. Yet given the great improvements in health that decelerated ageing could provide, it would seem that the only possible ethical course is to pursue it energetically. Thus, decelerated ageing has an element of tragic inevitability: its benefits to health compel us to pursue it, despite the transformation of human society, and even human nature, that this could entail.     

Mitochondrial involvement in the ageing process. Facts and controversies

Mitochondria are believed to be involved in human ageing. Whilst it is clear that various mitochondrial DNA mutations do accumulate in human tissues with age, whether or not they interfere with respiratory chain function is uncertain. We question the results of previous studies which have measured respiratory chain function in human skeletal muscle with age. Whilst cytochrome c oxidase deficient fibres are a real finding in skeletal muscle, the contribution of mitochondrial DNA mutations to human ageing is still controversial. Our results show for mitochondria to be involved in ageing then it must be through a more subtle mechanism than a global decline in respiratory chain function. (Mol Cell Biochem 174: 325–328, 1997)     

TOR and ageing: a complex pathway for a complex process

Studies in invertebrate model organisms have led to a wealth of knowledge concerning the ageing process. But which of these discoveries will apply to ageing in humans? Recently, an assessment of the degree of conservation of ageing pathways between two of the leading invertebrate model organisms, Saccharomyces cerevisiae and Caenorhabditis elegans, was completed. The results (i) quantitatively indicated that pathways were conserved between evolutionarily disparate invertebrate species and (ii) emphasized the importance of the TOR kinase pathway in ageing. With recent findings that deletion of the mTOR substrate S6K1 or exposure of mice to the mTOR inhibitor rapamycin result in lifespan extension, mTOR signalling has become a major focus of ageing research. Here, we address downstream targets of mTOR signalling and their possible links to ageing. We also briefly cover other ageing genes identified by comparing worms and yeast, addressing the likelihood that their mammalian counterparts will affect longevity.     

Extensive clonal spread and extreme longevity in saw palmetto, a foundation clonal plant

The lack of effective tools has hampered out ability to assess the size, growth and ages of clonal plants. With Serenoa repens (saw palmetto) as a model, we introduce a novel analytical framework that integrates DNA fingerprinting and mathematical modelling to simulate growth and estimate ages of clonal plants. We also demonstrate the application of such life-history information of clonal plants to provide insight into management plans. Serenoa is an ecologically important foundation species in many Southeastern United States ecosystems; yet, many land managers consider Serenoa a troublesome invasive plant. Accordingly, management plans have been developed to reduce or eliminate Serenoa with little understanding of its life history. Using Amplified Fragment Length Polymorphisms, we genotyped 263 Serenoa and 134 Sabal etonia (a sympatric non-clonal palmetto) samples collected from a 20 × 20 m study plot in Florida scrub. Sabal samples were used to assign small field-unidentifiable palmettos to Serenoa or Sabal and also as a negative control for clone detection. We then mathematically modelled clonal networks to estimate genet ages. Our results suggest that Serenoa predominantly propagate via vegetative sprouts and 10,000-year-old genets may be common, while showing no evidence of clone formation by Sabal. The results of this and our previous studies suggest that: (i) Serenoa has been part of scrub associations for thousands of years, (ii) Serenoa invasion are unlikely and (ii) once Serenoa is eliminated from local communities, its restoration will be difficult. Reevaluation of the current management tools and plans is an urgent task.     

Toll-Like Receptors and Human Disease: Lessons from Single Nucleotide Polymorphisms

Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease.     

Human longevity and common variations in the LMNA gene: a meta-analysis

A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson-Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA's possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (LLI) (US Caucasians with age ≥ 95 years, N=873) and genetically matched younger controls (N=443). We tested all common nonredundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on four SNPs, remained significant after adjustment for multiple testing (OR=1.56, P=2.5 × 10(-5) , multiple-testing-adjusted P=0.0045). To attempt to replicate these results, we genotyped 3619 subjects from four independent samples of LLI and control subjects from (i) the New England Centenarian Study (NECS) (N=738), (ii) the Southern Italian Centenarian Study (SICS) (N=905), (iii) France (N=1103), and (iv) the Einstein Ashkenazi Longevity Study (N= 702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR=1.60, P=0.0023), but not in the other three samples (P > 0.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR=1.18, P=7.5 × 10(-4) , multiple-testing-adjusted P=0.037). These results suggest that LMNA variants may play a role in human lifespan.     

Pollen viability and longevity: Practical, ecological and evolutionary implications

The present article reviews the various definitions and terminology of pollen viability and longevity as well as the various tests of its assessment. We compare the advantages and the disadvantages of each method and suggest some practical implications as revealed by the extensive data. We recognize eight main hypotheses concerning the ecology and the evolution of pollen longevity and critically evaluated them according to the literature. The hypotheses are grouped as follows: (1) Desiccation risk-carbohydrate content; (2) Pollen packaging; (3) Pollen competitive ability; (4) Pollinator activity-stigma receptivity duration; (5) Self-pollination chance; (6) Pollen exposure schedule; (7) Pollen travel distance, and (8) Pollen removal chance.     

Size,longevity and cancer: age structure

There is significant recent interest in Peto''s paradox and the related problem of the evolution of large, long-lived organisms in terms of cancer robustness. Peto''s paradox refers to the expectation that large, long-lived organisms have a higher lifetime cancer risk, which is not the case: a paradox. This paradox, however, is circular: large, long-lived organisms are large and long-lived because they are cancer robust. Lifetime risk, meanwhile, depends on the age distributions of both cancer and competing risks: if cancer strikes before competing risks, then lifetime risk is high; if not, not. Because no set of competing risks is generally prevalent, it is instructive to temporarily dispose of competing risks and investigate the pure age dynamics of cancer under the multistage model of carcinogenesis. In addition to augmenting earlier results, I show that in terms of cancer-free lifespan large organisms reap greater benefits from an increase in cellular cancer robustness than smaller organisms. Conversely, a higher cellular cancer robustness renders cancer-free lifespan more resilient to an increase in size. This interaction may be an important driver of the evolution of large, cancer-robust organisms.     

Genetic,historical and linguistic perspectives on the origin of the Kelantanese Malays

The Kelantanese Malays who resided in the remote northeastern regions of the Malay Peninsula in the Kelantan state are believed to have a unique genetic signature. The objective of this review is to analyze the populational sub-structure of the Kelantanese Malays from historical, genetic and linguistic perspectives. Historical data suggest that the Semang were composed of the Jahai, Bateq and Kensiu sub-tribes, whereas the Senoi were composed of only the Temiar sub-tribe. The Mendriq sub-tribe is believed to be the first group of aborigines to land in Kelantan. Subsequently, genetic analysis showed that the Kelantanese Malays are an independent clade at the base of the phylogenetic tree and contain genetic material similar to that of the Semang, specifically the Jahai and the Kensiu sub-tribes. The genetic data are supported by the fact that the Aslian language, a branch of the Austroasiatic languages that is widely spoken by the Semang, was potentially transmitted through agricultural activities. However, the potential limitation of this mini-review is the lack of primary reliable sources covering the historical, linguistic and genetic features of the Kelantanese Malays.     

Cloning, Sequencing, and Transgenic Expression ofPodospora curvicollaandSordaria macrosporaeEF1A Genes: Relationship between Cytosolic Translation and Longevity in Filamentous Fungi

We have cloned and sequenced the gene encoding the translation elongation factor eEF1A from two filamentous fungi,Podospora curvicollaandSordaria macrospora.These fungi are close relatives ofPodospora anserinaand also show senescence syndromes. Comparison of the sequences of the deduced proteins with that ofP. anserinareveals that the three proteins differ in several positions. Replacement of theP. anserinagene by either of the two exogenous genes does not entail any modification inP. anserinaphysiology; the longevity of the fungus is not affected. No alteration ofin vivotranslational accuracy was detected; however, the exogenous proteins nonetheless promoted a modification of the resistance to the aminoglycoside antibiotic paromomycin. These data suggest that optimization of life span between these closely related fungi has likely not been performed during evolution through modifications of eEF1A activity, despite the fact that mutations in this factor can drastically affect longevity.     

The effects of moisture and temperature on the ageing kinetics of pollen: interpretation based on cytoplasmic mobility

This study shows that characterization of the molecular mobility in the cytoplasm of pollen provides a new understanding of the effects of moisture and temperature on ageing rates. Using EPR spectroscopy, we determined the rotational motion of the polar spin probe, 3-carboxy-proxyl, in the cytoplasm of Typha latifolia pollen, under different temperature and moisture content conditions. Increasing the temperature resulted in faster rotational motion, analogous to faster ageing rates. With decreasing moisture content, rotational motion first decreased until a minimum was reached, after which rotational motion slightly increased again. The moisture content at which this minimal rotational motion was observed increased with decreasing temperature, comparable to the pattern of ageing rate. A significant linear relationship was found between ageing rates and rotational motion in the cytoplasm, suggesting that these parameters are causally linked. Upon melting of the intracellular glass, a twofold increase in activation energy of rotational motion and ageing rate was observed. In contrast, melting of the sucrose glass resulted in an increase in rotational motion of five orders of magnitude. The difference in rotational motion upon melting glasses of pollen or sucrose suggests that other molecules beside sugars play a role in intracellular glass formation in pollen.     

Cloning Heterologous Genes: Problems and Approaches

Model fungi such asNeurospora crassa, Aspergillus niger,andSaccharomyces cerevisiaehave provided a wealth of genetic information and are currently the object of cooperative genome sequencing projects. Many agriculturally and medically economic important pathogenic fungi, however, are less well characterized, which makes it difficult to study their genes and gene products. Gene sequences from model fungi offer a unique opportunity to clone cognate genes from pathogenic counterparts. In this review, we propose three basic strategies for cloning such genes: Functional complementation, sequence similarity, and genetic linkage. These strategies involve Southern hybridization, cloning, library screening, genetic complementation, and the polymerase chain reaction. We review the major problems encountered using these strategies and outline useful solutions to these difficulties.     

Fish Trypanosomes: Their Position in Kinetoplastid Phylogeny and Variability as Determined from 12S rRNA Kinetoplast Sequences

Fish trypanosomes have traditionally been classified according to the host species from which they were isolated, each isolate being regarded as a distinct species. To test the soundness of this practice, the genetic variabilities of the kinetoplast 12S rRNA-encoding genes of different fish trypanosomes isolates were compared. The DNAs were extracted from trypanosomes cloned from blood samples of 15 donors representing ten different fish species in four orders from waters of three major river systems of Central and Northern Europe. Comparison with other trypanosomatid sequences revealed that the fish trypanosomes form a monophyletic group with Trypanosoma brucei as a sister group. Pairwise comparisons of genetic distances yielded a wide range of continuous variation with no indication of any discontinuities attributable to barriers to gene flow. The genetic distances did not correlate with either the identity of the host species or geography. The host specificity of fish trypanosomes appears to be limited.