Looking Beyond Rapamycin at the Effects of Other Anti-Cancer Agents on Aging

There is some debate over whether rapamycin, an immune suppressant agent that is presently being used in research to inhibit the activities of the protein produced by the mechanistic target of rapamycin (mTOR) gene, causes a slowing of aging or merely a reduction in cancer rates. The mTOR gene is a hot topic in research these days, as the extension of life in mice resulting from rapamycin is more reliable and easily replicated than is presently the case for any other line of longevity-enhancing drug development. The question of whether it actually slows aging or merely suppresses cancer is somewhat important for the future of this research, however. Both outcomes produce longer life in laboratory animals, but only one is of great interest to longevity science - if rapamycin is only a cancer suppressant, then its continued development will be picked up by the cancer research community, and the scientists aiming at aging will move on.

This runs the other way as well, of course. If there is debate over whether a cancer suppressant is slowing aging or not, then you will find researchers who think that perhaps it is time to take a closer look at how other known or suspected cancer suppressants work. Might they be slowing aging? This attitude is prevalent among researchers who subscribe to the programmed view of aging, seeing degenerative aging as something that might ultimately be stopped entirely through suitable alterations to genetic programming and protein levels. Digging through the enormous complexity of metabolism and its relationship with degenerative aging is much more attractive if you imagine that this sort of grail lies at the end of the road.

This research group advocates the hyperfunction theory of programmed aging, and its members see extension of life through inhibition of mTOR as supportive of that theory:

Selective anticancer agents suppress aging in Drosophila

According to our analysis of the literature more than 100 pharmaceutical substances that can prolong the lifespan of model organisms [have been discovered]. However, the increase of lifespan with aging-suppressor substances rarely exceeds 40%, which [is] greatly less than effects (up to 1000% or more) caused by mutations in the regulatory genes, which are the key switches of cell program to maintain growth or resist to stress, such as gene of PI3Ksubunit. We proceeded on the assumption that a more effective aging-suppressor drugs may be substances with specificity to the products of genes that control the evolutionarily conserved mechanisms of aging, mutations in which have the greatest effect on lifespan and the aging rate. In this regard, we investigated the aging-suppressive properties of specific pharmacological inhibitors of aging associated gene products TOR, PI3K, NF-κB and iNOS.

The aging process is associated with hyperactivation of TOR and PI3K, as well as NF-κB and iNOS, leading to cellular senescence, age-related pathologies, and oncogenesis. Therefore, many anticancer agents are inhibitors of the same enzymes as aging-suppressors, including TOR, PI3K, NF-κB and iNOS. This is entirely consistent with the theory that considers cellular senescence as age-dependent hyperactivation of pro-aging signaling pathways.

We studied the effects of inhibitors of PI3K (wortmannin), TOR (rapamycin), iNOS (1400W), NF-κB (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors [on] Drosophila melanogaster lifespan and quality of life (locomotor activity and fertility). Our data demonstrate that pharmacological inhibition of PI3K, TOR, NF-κB, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin and wortmannin (by 23.4%). The bioinformatic analysis showed the greatest aging-suppressor activity of rapamycin, consistent with experimental data.

The programmed aging viewpoint must be contrasted with the view that aging is an accumulation of damage. We see changes in protein levels and epigenetic alterations with aging because metabolism reacts to that damage - damage causes change, the reverse of the programmed aging view of change leading to damage. If, as I believe from my reading around the field, aging is indeed largely a matter of a stochastic accumulation of unrepaired damage, then manipulation of genes and metabolism to try to slow down aging is a very poor way forward in comparison to just fixing the damage. Building methods of repair for the known forms of damage that cause aging should be a far easier and faster development program - which is why I support SENS over mainstream work on the development of longevity drugs. It is the more optimal path forward, and the only one likely to lead to radical life extension in our lifetimes.

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