A Perspective On Genetics and Aging

Aging researchers Leonid Gavrilov and Natalia S. Gavrilova have posted a draft on genetics and aging to Longevity Science. Recall that these two are behind the reliability theory of aging; I find their perspectives are usually quite different to those at the biogerontological end of the research community. If I had to sum it up in a few words, these researchers work somewhere toward the more analytical end of the triangle formed by systems theory, biogerontology and actuarial studies. Differing perspectives are hard to create and their collision is often the source of new insight - therefore they are valuable.

In molecular genetic studies of human aging traits, the gene association studies remain the most common research approach. In these studies the effect of candidate genes on longevity is analyzed by comparing gene frequencies between affected individuals (cases) and unaffected control individuals. Comparison of candidate gene frequencies among centenarians and younger controls is a typical example of such studies. Another molecular genetics approach - the genome-wide linkage scan of genes, is a relatively new direction of research. Linkage analysis is a mapping of genetic loci using observations of related individuals (pairs of affected and nonaffected siblings, for example). This direction of research has a potential for obtaining interesting results, although the success of genome-wide scans of complex human diseases requires large sample sizes, considerable effort and expense.

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A review of gene-longevity association studies revealed that different studies often produced inconsistent and even contradictory results.

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Most chronic diseases in later life are complex multifactorial disorders. Multifactorial disorders are influenced by multiple genes, often coupled with the effects of environmental factors. Many diseases common to old age, such as late-onset Alzheimer's disease, heart disease, diabetes are now considered to be multifactorial disorders. Most genes associated with multifactorial disorders have low penetrance, which means that the likelihood of developing disease among genotype carriers is low. Thus, the individuals with disease-related genes do not necessarily succumb to disease. With favorable lifestyle and environment there is an opportunity for individual with genetic risk factor to delay and even to avoid the disease.

All of which suggests we should be realistic when it comes to the likelihood of finding any simple correlations within the fantastically complex system formed by a lifetime of interaction between genes, the machinery that carries out their programming, and the world within which the resulting humans operate.

Not to harp on the same point over and over, but this helps to demonstrate why it is imperative we do all we can to intelligently reduce the complexity of our attempts to extend the healthy human life span. Categorizing changes in our biochemistry with age and developing the means to revert or repair those changes is a good deal less complex than either (a) gaining a complete understanding of human biochemistry or (b) attempting to change that biochemistry to produce the damage of age more slowly.

To put it more clearly, why does it matter exactly how it is our metabolism develops broken mitochondrial DNA with age if we have identified that change as pivotal and important, and know how to develop the means to repair it? Let's repair it first, then worry about the rest of the picture. It's important to get the priorities straight.

People built good, workable bridges long before the development of mathematical and engineering tools required to formally determine the best bridge-building strategy in any given case. Engineering our way to a cure for aging is no different in essence: good results are possible in the absence of complete understanding of the system, and by constraining the complexity of the work, it becomes much more plausible to see significant progress in our lifetimes.

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