Anti-aging: senolytics or gerostatics (unconventional view).

Mikhail V Blagosklonny

doi:10.18632/oncotarget.28049

Abstract

Senolytics are basically anti-cancer drugs, repurposed to kill senescent cells selectively. It is even more difficult to selectively kill senescent cells than to kill cancer cells. Based on lessons of cancer therapy, here I suggest how to exploit oncogene-addiction and to combine drugs to achieve selectivity. However, even if selective senolytic combinations will be developed, there is little evidence that a few senescent cells are responsible for organismal aging. I also discuss gerostatics, such as rapamycin and other rapalogs, pan-mTOR inhibitors, dual PI3K/mTOR inhibitors, which inhibit growth- and aging-promoting pathways. Unlike senolytics, gerostatics do not kill cells but slow down cellular geroconversion to senescence. Numerous studies demonstrated that inhibition of the mTOR pathways by any means (genetic, pharmacological and dietary) extends lifespan. Currently, only two studies demonstrated that senolytics (fisetin and a combination Dasatinib plus Quercetin) extend lifespan in mice. These senolytics slightly inhibit the mTOR pathway. Thus, life extension by these senolytics can be explained by their slight rapamycin-like (gerostatic) effects.

Highlights

Spiced up with words like “emerging” and “promising” [1,2,3,4], numerous excellent reviews on senolytics can be friendly parodied in one sentence: ‘New promising strategies to fight devastating diseases are rapidly emerging, fueling new hopes and promising healthier lifespan with potential benefits to win the war on aging by using emergent senomorphics and promising senolytics’
A combination of Dasatinib plus Quercetin (D+Q) increased median lifespan from 937 days to 996 days in mice. This modest increase in lifespan can be explained by killing of senescent cells, and by off-target effects such as mTOR inhibition. These senolytics are available for human use and, for reasons discussed elsewhere [7], can be used for life extension in humans without the need for lifelong clinical trials
Given that current senolytics may work as gerostatics, the significance of killing of senescent cells is unclear, even if it occurs (Figure 3)

Summary

Introduction

Spiced up with words like “emerging” and “promising” [1,2,3,4], numerous excellent reviews on senolytics can be friendly parodied in one sentence: ‘New promising strategies to fight devastating diseases are rapidly emerging, fueling new hopes and promising healthier lifespan with potential benefits to win the war on aging by using emergent senomorphics and promising senolytics’.Despite these promises, only two studies showed lifespan extension by senolytics in mammals. This modest increase in lifespan can be explained by killing of senescent cells, and by off-target effects such as mTOR inhibition. The term senolytics, drugs that selectively kill senescent cells, was introduced by Kirkland and Tchkonia in 2015 [8]. Senolytics must extend lifespan by killing senescent cells, not by off-target mechanisms [8].

Results

Conclusion