A Brace of Papers from the Longevity Genetics Community
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You'll find quite a few papers on longevity and genetics in the preprint queue of Current Vascular Phamacology at the moment. This is a portion of the output of that part of the research community focused on developing a full understanding of the molecular biology of how aging progresses and varies between individuals and species. Biology is fantastically complex, and obtaining that full understanding will be a much, much more challenging endeavor than merely successfully treating or reversing aging.

Treating and even curing aging are goals that might be achieved without a full understanding of exactly how aging progresses. Consider this: you don't need anything even close to a full molecular model of the progression of rust to greatly extend the life of metal equipment through scrubbing and protective coating. Exactly the same argument about knowledge and action can be applied to biology and medicine. Knowing what the damage is and having a complete understanding of how that damage progresses to cause the visible symptoms of aging are two very different things, the latter much more complex than the former, and only the former actually needed to produce useful therapies.

Nonetheless, most of the present work and funding in the aging science community is focused on developing an understanding of how degenerative aging progresses, not on damage repair and treatment of aging. So most of the output of the research community looks much along the lines of these first few papers I'm going to point out today.

The Challenges in Moving from Ageing to Successful Longevity

During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better health during their lifespan compared with contemporaries who died at a younger age?, 3) Do centenarians have protective modifications of body composition, fat distribution and energy expenditure, maintain high physical and cognitive function, and sustained engagement in social and productive activities?, 4) Do centenarians have genes which contribute to longevity?, 5) Do centenarians benefit from epigenetic phenomena?, 6). Is it possible to influence the transgenerational epigenetic inheritance (epigenetic memory) which leads to longevity?, 7) Is the influence of nutrigenomics important for longevity?, 8) Do centenarians benefit more from drug treatment, particularly in primary prevention?, and, 9) Are there any potential goals for drug research?

Genes Of Human Longevity: An Endless Quest?

Human longevity is a complex trait which genetics, epigenetics, environmental and stochasticity differently contribute to. To disentangle the complexity, our studies on genetics of longevity were, at the beginning, mainly focused on the extreme phenotypes, i.e. centenarians who escaped the major age-related diseases compared with cross sectional cohorts.

In association studies on candidate genes many SNPs, positively or negatively correlated with longevity have been identified. On the other hand, the identification of longevity-related genes does not explain the mechanisms of healthy aging and longevity, but it opens a huge amount of questions on epigenetic contribution, gene regulation and the interactions with essential genomes, i.e. mitochondrial DNA and microbiota.

Centenarian Offspring: a model for Understanding Longevity

A main objective of current medical research is the improving of life quality of elderly people as priority of the continuous increase of ageing population. Accordingly, the research interest is focused on understanding the biological mechanisms involved in determining the positive ageing phenotype, i.e. the centenarian phenotype.

Centenarians have been used as an optimal model for successful ageing. However, it is characterized by several limitations, i.e. the selection of appropriate controls for centenarians and the use itself of the centenarians as a suitable model for healthy ageing. Thus, the interest has been centered on centenarian offspring, healthy elderly people. They may represent a model for understanding exceptional longevity for the following reasons: to exhibit a protective genetic background, cardiovascular and immunological profile as well as a reduced rate of cognitive decline than age-matched people without centenarian relatives.

Phenotypes and Genotypes of High Density Lipoprotein Cholesterol in Exceptional Longevity

A change in the lipoprotein profile is a metabolic hallmark of aging and has been the target for modern medical developments. Although pharmaceutical interventions aimed at lipid lowering substantially decrease the risk of cardiovascular disease, they have much less impact on mortality and longevity. Moreover, they have not affected death from other age-related diseases.

In this review we focus on high density lipoprotein (HDL) cholesterol, the levels of which are either elevated or do not decrease as would be expected with aging in centenarians, and which are associated with lower prevalence of numerous age-related diseases; thereby, suggesting a potential HDL-mediated mechanism for extended survival. We also provide an update on the progress of identifying longevity-mediating lipid genes, describe approaches to discover longevity genes, and discuss possible limitations. Implicating lipid genes in exceptional longevity may lead to drug therapies that prevent several age-related diseases, with such efforts already on the way.

It has to be said, however, that some areas of research are close enough to the development of actual rejuvenation treatments - those addressing at least some of the root cause damage of aging rather than downstream consequences - that even the scientific mainstream is coming around to the idea. The impact of cellular senescence on aging is one such field, as several obvious and existing applications of medical technology may aid in removal of the senescent cells that accumulate with age, and early work in mice confirms that such treatments should prove helpful:

Cellular Senescence in Ageing, Age-Related Disease and Longevity

Cellular senescence is the state of permanent inhibition of cell proliferation. There is mounting evidence that senescent cells contribute to ageing and age-related disease by generating a low grade inflammation state (senescence-associated secretory phenotype-SASP). Even though cellular senescence is a barrier for cancer it can, paradoxically, stimulate development of cancer via proinflammatory cytokines. There is evidence that senescent vascular cells, both endothelial and smooth muscle cells, participate in atherosclerosis and senescent preadipocytes and adipocytes have been shown to lead to insulin resistance.

Thus, modulation of cellular senescence is considered as a potential pro-longevity strategy. It can be achieved in several ways like: elimination of selected senescent cells, epigenetic reprogramming of senescent cells, preventing cellular senescence or influencing the secretory phenotype. Some pharmacological interventions have already been shown to have promising activity in this field.

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