Fight Aging!

Here, find an examination of the current state of senolytic drug candidates, compounds capable of selectively destroying senescent cells. All of those established by the research community appear to work by provoking lingering senescent cells into taking the final steps into apoptosis and self-destruction. Near all senescent cells in fact undergo apoptosis on their own, or are destroyed by the immune system. The few that remain seem primed for apoptosis, but are held back by a small number of inhibitor mechanisms. Drugs that target those mechanisms have been shown to clear up to 50% of senescent cells from aged tissues, the actual amount varying widely by tissue and drug type - in some tissues, the effect is negligible for the drugs tried to date.

The accumulation of senescent cells with age is one of the root causes of degenerative aging and age-related disease. These cells secrete a harmful mix of signals that promote inflammation, disorder extracellular matrix structures required for correct tissue function, and encourage bad behavior in nearby normal cells. In older individuals, this becomes a significant driver of the damage of aging. The most straightforward approach to this problem is to remove these unwanted cells; they are only a fraction of most tissues, and so can be safely cleared out. Studies in mice have demonstrated an extension of healthy life and reversal of aspects of aging through the use of senolytic therapies; it is an exciting field.

Aging at the cellular level is called "cell senescence", and it contributes profoundly to whole-body aging. The most promising near-term prospects for a leap in human life expectancy come from drugs that eliminate senescent cells. Programs in universities and pharmaceutical labs around the world are racing to develop "senolytic" drugs, defined as agents that can kill senescent cells with minimal harm to normal cells.

By analogy with chemotherapy for cancer, the value of a senolytic treatment is measured by its ability to kill senescent cells without doing harm to normal cells. The index called SI50 (SI for "selectivity index - 50%") is defined by analogy to LD50, the "lethal dose" of a toxin, the dose at which half of all cells die. SI50 is defined as the ratio of LD50 for normal cells and LD50 for senescent cells. It is the concentration of the agent at which half the normal cells die, divided by the concentration at which half the senescent cells die. A recent study in which researchers killed senescent cells by interfering in the crosstalk between FOXO4 and P53 reported an SI50 about 12. My guess is that 12 is an encouraging beginning, but it is not high enough to support a useful therapy.

The encouraging fact is that, at the optimal dose, more than 80% of the senescent cells have succumbed to apoptosis, while the number of eliminated normal cells is still below detection. Unfortunately, senolytic agents studied previously, including dasatinib, quercetin and ATTAC, did not include measurements of SI50 that we might use for comparison. The authors of the FOXO4 study were in a rush to publish. They used a fast-aging strain of mice, and even for these, they did not wait to see survival curves. The indicatators of rejuvenation that they do report look positive: increased activity levels, regrowth of lost fur, and improvement of kidney function lost with age.

I had missed the two papers about senolytic drug candidates ABT-263 and ABT-737. Both ABT-263 and ABT-737 were identifed in screens for agents that block BCL-2. BCL-2 is the founding member of another family of proteins that signal a cell to resist apoptosis. The ABT-263 paper included some in vivo results, indicating enhanced growth of blood stem cells after senescent cells have been removed. In vivo testing of ABT-737 was limited. Neither group reports the selectivity index (SI50), but from graphs that they do present, it is clear that ABT-263 is more selective than ABT-737, and that neither is as selective as the more recent FOXO4 method.

The idea of removing senescent cells has a lot of appeal, and enjoys broad empirical support in mammals. There is now a world-wide effort, making rapid progress toward specificity in senolytic treatments. The FOXO4 approach involves the newest agent, and it shows the best ratio yet for killing senescent cells while avoiding collateral damage to healthy cells. It cannot be taken orally and must be injected, but perhaps this is not such a drawback for a treatment that is needed only intermittently, every few years. How will such promising mouse results translate into human health and life extension? We have as yet no data, not even anecdotes. But perhaps we are near the point where hope and courage will motivate the first self-experimenting volunteers. This is a fast-moving field in which researchers are in a rush to publish and (presumably) pharmaceutical companies are taking pains to keep their results hushed up. Sharing of information and resources could push this research over the top and give us the first full decade of human life extension.

Link: https://joshmitteldorf.scienceblog.com/2017/03/28/senolytics-against-aging-snapshot-of-a-fast-moving-field/