Friday, April 25, 2008

Aging Cell Article on Longevity Genes

The latest issue of Aging Cell has this excellent Review piece which is currently available online for free. It's titled "Genes encoding longevity: from model organisms to humans" by Maris Kuningas et. al. Here is the summary:

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.

And here is a sample from the article:

Over the last century, the mean life expectancy in Western societies has increased dramatically (Oeppen & Vaupel, 2002). In Japan, for instance, the mean life expectancy has increased from 50 years to 80 years in no more than six decades. It is unlikely that changes in the population genome over this time-period can explain for the observed increase in lifespan which is more likely to be attributable to the improvement of environmental conditions and medical care. The increase in mean life expectancy of the total population, however, has left the marked interindividual variance in lifespan unaltered. Socio-economic factors can in part explain this phenomenon, but ample evidence suggests that genetic factors are also at play. Studies of twins and long-lived families have estimated that 20–30% of the variation in human lifespan is determined by genetic factors, which impact becomes more important for survival at older ages (Herskind et al., 1996; Mitchell et al., 2001; Hjelmborg et al., 2006). Furthermore, siblings of centenarians have a significantly higher chance of becoming a centenarian themselves when compared to other members of their birth cohort (Perls et al., 2002). The survival benefits of family members of these long-lived subjects are lifelong and persist up to the highest age categories (Perls et al., 2002; Hjelmborg et al., 2006). Offspring of long-lived sibling pairs have a lower mortality risk already at middle age, whereas their spouses, with whom they have shared in part a common environment, do not show this survival benefit (Schoenmaker et al., 2006).

As for lifespan, aging is under moderate genetic control influencing the rate at which stochastically induced damaged molecules accumulate. Such damage is caused by various endogenous and exogenous biological and biochemical stresses. As a result, over the life course there is a constant rise in vulnerability of the body, leading to a continuously increasing risk of disease and death. Longevity and the maintenance of health in old age can be ensured via two principally different strategies that minimize the risk of permanent damage to occur, that is, by a decrease of environmental hazards or an increase of the durability of the body. Pathways that influence metabolism, maintenance and repair mechanisms, and prevent the accumulation of permanent damage thus represent key molecular candidates for the preservation of health and longevity.

Experiments in model organisms have demonstrated that a series of induced mutations in various genes that make up an integrated molecular pathway can dramatically increase lifespan. The most prominent example includes the Caenorhabditis elegans daf-2 and clk double mutants that live nearly five times longer than wild-type worms (Lakowski & Hekimi, 1996). Most of the genes of model organisms are evolutionarily conserved and present in humans.

Fascinating stuff!