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Senolytic Drugs Can Become a Future Regenerative Medicine

Today I thought I'd share a recent commentary on cellular senescence research to treat aging. A growing amount of work is taking place on the fundamentals of clearing senescent cells as a method of partial rejuvenation. The presence of newly founded companies pushing forward towards clinical translation, and results showing life extension and improved tissue function in normal mice are drawing more funding into the field. Folk in our grassroots community are also helping where they can, such as by crowdfunding the first studies to be carried out by the Major Mouse Testing Program earlier this year, or providing seed funding for promising companies. All of this effort is not before time: it is nearing fifteen years since SENS rejuvenation biotechnology advocates first gathered the evidence supporting senescent cell accumulation as a fundamental cause of aging, and began calling for more research on this topic. Various research groups are now focusing on different methods of clearance and their effects on specific tissues and organs, seeking to prove or disprove effects on degenerative aging. We should expect to see a mix of benefits and absence of benefits once the dust settles: senescent cells are only one of the seven broad classes of age-related damage enumerated in the SENS research proposals. Their presence may contribute to many or even all of the common age-related conditions, but they are not significant causes of all of the specific forms of secondary and later cell and tissue dysfunction in the aging body.

To pick one example, earlier this year researchers published a study of the effects of reduced senescent cell counts on aspects of vascular aging. It was indeed a mix of benefits and absence of effects: fewer senescent cells led to reduced calcification of blood vessel walls, associated with blood vessel stiffening with age, but it didn't have much of an impact on the development of atherosclerotic plaques. Both of these items are about as serious in their consequences over the long run. Stiffening of blood vessels drives hypertension, which in turn produces damage to delicate tissues such as the brain and kidneys as tiny blood vessels suffer structural failure at a greater rate. It also provokes remodeling of heart tissue, leading to heart failure, and along the way helps to turn atherosclerosis into a fatal condition. The fatty, inflamed plaques that distort blood vessels eventually grow to the point of rupture, which either blocks or breaks important large vessels. That is a frequently fatal occurrence. This mixed outcome was an interesting result, as one of the characteristics of senescent cells is that they produce greater levels of chronic inflammation via the mix of signals they generate, the senescence-associated secretory phenotype. This signaling is how small numbers of senescent cells, perhaps 1% of the cells present in an organ, can distort the function of the other 99%. Inflammation is pretty important to the pace of progression of atherosclerosis, so one might expect a reduction in the number of senescent cells to slow the pace of that condition - but apparently not in this particular scenario.

The recently published commentary linked below is a celebration of the fact that the scientific community has finally achieved some traction in the matter of a treatment for the root causes of aging, one likely to produce reliable, if partial, degrees of rejuvenation. It is not unreasonable at this point to expect senescent cell clearance to achieve larger and more robust results on aging and age-related disease than much of the rest of present day medicine, and to do so in a way that is additive to other methodologies. That capability will emerge fairly soon in clinics, a few years to a decade from now, varying with the regulatory environment and where the products are offered. This is the true benefit of focusing on reverting the fundamental damage that is the cause of aging, rather than tinkering with later stages of disease and malfunction.

Senescent cell death brings hopes to life

Life expectancy in the developed countries is continuously increasing. However, age-related diseases lead to late life complications and remain the most prevalent cause of mortality. One of the cellular components that is present in sites of age-related pathologies and accumulates during aging is senescent cells. These cells are formed when a stress signal triggers terminal cell cycle arrest in proliferating cells. Entrance to a state of senescence deprives damaged cells of their proliferative potential and thus limits tumorigenesis and tissue damage. Despite the protective role of cellular senescence, the long term presence of senescent cells is harmful to their environment. These cells secrete a plethora of pro-inflammatory factors that might aid their removal by the immune system. However, at advanced age senescent cells gradually accumulate in tissues and the secretory phenotype promotes a chronic "sterile" inflammation which is a hallmark of unhealthy aging. Elimination of senescent cells in mice by a genetic approach led to a decreased burden of age-related disorders, and an increased median survival of the mice. Therefore, pharmacological elimination of senescent cells in-vivo is a promising strategy for treatment of age-related diseases associated with accumulation of senescent cells. An attractive method to implement this strategy would be to induce apoptosis preferentially in senescent cells. The scientific basis of this approach relies on an understanding of the molecular mechanisms that distinguish the regulation of apoptosis in senescent cells from other cells.

Resistance of senescent cells to both extrinsic and intrinsic pro-apoptotic stimuli testifies for complex regulation of apoptosis in these cells. We recently demonstrated that senescent cells, induced to senesce by different kind of insults, upregulate proteins of the anti-apoptotic BCL-2 family. Combined knockdown of these proteins or their inhibition by a small molecule inhibitor, ABT-737, selectively skew cell-fate decision in senescent epithelial cells in-vivo toward apoptosis. Therefore, the expression of BCL-2 family members endowed senescent cells with resistance to apoptosis. The senolytic activity of the ABT-737 molecule was demonstrated in in-vivo models of senescence. DNA damage-induced senescent cells were formed in the lungs upon ionizing irradiation of mice. Administration of ABT-737 rapidly reduced the number of senescent cells, concomitantly with an increase in apoptosis.

Alongside with the BCL-2 family inhibitors, other approaches for selective elimination of senescent cells, also termed senolytic approaches, have been identified. For example, the combination of 2 drugs, dasatinib and quercetin, was shown to exert killing potential of senescent preadipocyte and endothelial cells. Elimination of senescent cells could also be achieved by adapting tools from the field of cancer therapy. One such possibility is utilization of common immunotherapy practices following identification of senescence-specific markers. The immune system is a natural resource that is able to recognize and eliminate senescent cells. Using its properties in combination with immunotherapy approaches or with emerging senolytic drugs might lead to more specific and efficient elimination of senescent cells. However, no matter what would be the approach of choice, it is necessary to keep in mind that senescent cells participate in variety of essential physiological functions such as in wound healing, tumor suppression, regulation of glucose levels and embryonic development. In order to develop efficient senolytic approaches it is necessary to dissect beneficial and detrimental functions of senescent cells in different physiological and pathophysiological conditions using in-vivo models.

Successful development of senolytic drugs will bring senescent cells to the forefront of anti-aging therapies. However, it is necessary to understand the effect of elimination of senescent cells on diverse cell communications in the complex tissues. Elimination of senescent cells by ABT-737 or ABT-263 was followed by increased proliferation of stem cells in both skin and haematopoietic system. These results suggest that senolytics can have an impact on tissue regeneration and can potentially be used in regenerative medicine. This approach will combine elimination of damaged cells with stimulation of proliferation of healthy progenitors, in a way that could restore tissue fitness in diseases associated with reduced tissue function. In summary, senolytic drugs can become a future regenerative medicine. Treatment with senolytic drugs results in the elimination of senescent cells, thus blocking tissue degeneration and late life complications. In turn, elimination of senescent cells leads to the proliferation of stem cells, allowing tissue regeneration. This joined effect of senolytic drugs will restore tissue fitness and will help restraining age-related pathologies.

Comments

@Reason,

Any thoughts on what the next 1 or 2 treatments would be after cellular senescence treatments and how far down the road they could be available here or abroad? I think the first one will be really exciting and will creat huge discussion into aging and the feasability of repairing it as opposed to slowing it down.

I would think once the first treament (out of 7) of cellular senescence research becomes available to the general public, the publicity should greatly encourage more funds into getting the other 6 causes of aging quickly into treatments also. Or not.

Posted by: Robert at October 20th, 2016 1:01 AM

Mmm, didn't know that senescent cells contribute to regulation of glucose levels.

Posted by: Antonio at October 20th, 2016 2:31 AM

Very good news. I hope that such dynamics in research and clinics will also be possible for other rejuvenation therapies once they are proven to have a rejuvenating effect by more and more groups. One thing I'd like to point out however: as the first rejuvenation therapies become available, we must not forget that we need biomarkers for the damage forms in our bodies, In this case, we need to be able to reliably measure the abundance and effect of senescent cells in the body. I mean whos Gonna need senolytics and at what dose?

Posted by: K. at October 20th, 2016 5:16 AM

I believe RepleniSENS is next, Stem cells research is very well funded and there are already many promising treatments in that field.

Posted by: RS at October 20th, 2016 7:39 AM

Stem cells are already here and in large scale use. The next SENS thing will be Senolytics without a doubt.

Posted by: Steve Hill at October 20th, 2016 8:25 AM

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