There are Many, Many Genes Associated with Longevity
Researchers have found hundreds of genes that can be manipulated to at least modestly extend longevity in various laboratory species, though the size of the effects diminish as species life span increases. Short-lived species have life spans that are far more plastic in response to environmental and genetic changes. Since proteins group into interaction networks, most of these genetic manipulations are different ways to adjust the same few core underlying processes. Mapping metabolism sufficiently to understand all of this is an ongoing process, but one that seems unlikely to contribute greatly the near future of human longevity. Unfortunately, adjusting the operation of metabolism is a poor path to the treatment of aging in comparison to repair of the molecular damage that causes aging: it can only slow aging, not reverse it; the past fifteen years have demonstrated that it is expensive and produces few useful therapies; the potential for additional years of healthy life is low. Nonetheless, it remains the primary focus of the research community.
Hundreds of genes, when manipulated, have been shown to affect the lifespan of model organisms (yeast, worm, fruit fly, and mouse). These genes, further denoted as longevity-associated genes, LAGs, could be defined as those whose modulation of function or expression results in noticeable changes in longevity - lifespan extension or accelerated aging. We have previously investigated the characteristic features of LAGs and found that (i) they display a marked diversity in their basic function and primary cellular location of the encoded proteins; and (ii) LAG-encoded proteins display a high connectivity and interconnectivity. As a result, they form a scale-free protein-protein interaction network ('longevity network'), indicating that LAGs could act in a cooperative manner.
Many LAGs, particularly those that are hubs in the 'longevity network', are involved in age-related diseases, including atherosclerosis, type 2 diabetes, cancer, and Alzheimer's disease, and in aging-associated conditions such as oxidative stress, chronic inflammation, and cellular senescence. The majority of LAGs established in yeast, worms, flies, and mice have human orthologs, indicating their conservation 'from yeast to humans'. This assumption was also supported by studies on specific LAGs or pathways such as Foxo, insulin/IGF1/mTOR signaling, Gadd45, and cell-cell and cell-extracellular matrix interaction proteins.
Now, the existing databases on orthologs allow for an essential extension of the analysis of LAG orthology, far beyond the traditional model organisms and humans. In particular, the data deposited in the InParanoid database Eukaryotic Ortholog Groups include orthologs for the complete proteomes of 273 species. Here, we report the results of an unprecedentedly wide-scale analysis of 1805 LAGs established in model organisms, available at Human Ageing Genomic Resources (HAGR) GenAge database, with regard to their putative relevance to public and private mechanisms of aging.
Our wide-scale analysis of longevity-associated genes (LAGs) shows that their orthologs are consistently overrepresented across diverse taxa, compared with the orthologs of other genes, and this conservation was relatively independent of evolutionary distance. Moreover, many worm LAGs were discovered by postdevelopmental RNA interefence on genes essential for growth and development, and this predominantly resulted in lifespan extension. That is, postdevelopmental suppression of genes that are vital early in life but are detrimental later in life, can be beneficial for longevity. The orthologs of these LAGs are also highly overrepresented across diverse taxa. Altogether, the C. elegans analysis suggests that antagonistic pleiotropy might be a highly conserved principle of aging.
An important observation in our study was that the majority of manipulations on LAG orthologs in more than one model animal resulted in concordant effects on longevity. This strengthens the paradigm of 'public' longevity pathways and of using model animals to study longevity, even across a large evolutionary distance. This notion is further strengthened when combined with the observation that the existence of an ortholog is probably accompanied by a preserved role in longevity. Yet, we also observed LAGs with ortholog presence only in a limited number of taxa, or that displayed discordant effects when tested in more than one species, which could, at least in part, be attributed to 'private' mechanisms of aging. Definitely, more comparative studies are warranted to better discriminate between private and public mechanisms, with unified methods of intervention and evaluation in mind.
There may be many genes involved in aging, but as the epi-geneticists say, all roads pass through AMPK, the controller of whether energy is stored or burned. Also, anything that inhibits NF-kappa B would be an anti-aging agent. Additionally, many anti-aging agents activate nitric oxide, an oxidant that signals the body via Nrf2 to turn on endogenous antioxidant defenses (glutathione, catalase, SOD, heme oxygenase). So there are keys to downstream gene targets. We already known some mammals can live 10 times longer than their kind (naked mole rat versus other rodents) and some humans live up to 40% longer than others. Short of achieving biological immortality, steps can be taken to meaningfully prolong the health span and lifespan of humans today which buys time for implementation of even more revealed anti-aging technologies in the future, as Aubrey de Grey has indicated.