Fight Aging!

Effective clearance of senescent cells in humans is arguably the form of SENS-style rejuvenation treatment based on repair of cell and tissue damage that is closest to practical implementation. A therapy capable of safely clearing even half of the senescent cells present in all tissues should prove very beneficial - and it is something that can be applied multiple times, as needed, repeatedly turning back this contribution to degenerative aging. As is always the case in these matters, however, only a few research groups are actively working on the problem, and funding is a desert in comparison to other areas of far less interesting research. This is why the research materials I'll point out here, news of a new potential class of senescent cell clearing drugs, still in the early stages of investigation, is worthy of attention rather than being buried by a score of similar announcements. In populous and comparatively well-funded fields such as the treatment of heart disease or arthritis there are far too many potential new drugs under study at an early stage in laboratories and noted in research papers to remark upon each of them. Few of these promising starts in cell cultures will ever get much further than that; there are many possible reasons why good results in cells don't translate to good results in animals. Similarly many of the promising results in animal studies fail on the next stage beyond that. So temper your enthusiasm.

Cells become senescent in response to damage, toxic environments, or as an alternative to self-destruction when they reach the end of their replicative life span. Some are destroyed by the immune system, but enough remain and linger that many tissues are made up of a sizable proportion of senescent cells by late life. These cells behave badly, secreting compounds that alter surrounding cellular activities, spur chronic inflammation, and degrade the extracellular matrix that is fundamental to tissue properties such as elasticity or load-bearing strength. Even partial and uneven clearance of senescent cells has been demonstrated in animal studies to provide lasting benefits to health following a single treatment. Better and more comprehensive clearance should produce greater benefits. That, of course, requires the development of improved methods of clearance.

The research materials quoted below can be taken as a representative sample of the sort of work that should be taking place in many more laboratories, an exploration in search of ever more effective ways to eliminate senescent cells from the body. Inevitably there will be dead ends, surprises, and much more failure than success. That is always the way in research. The way to make progress is to take many chances, invest in many diverse approaches to increase the overall odds of at least one useful result. Perhaps the most useful outcome here is that these results provide another solid demonstration that senescent cell clearance produces meaningful health benefits in aging mice. It is worth remembering that SENS rejuvenation research advocates have been calling for investment in this approach to the treatment of aging for more than a decade now, providing detailed research and development plans along with that advocacy, and were initially mocked for it in many quarters. Only in the last couple of years has the research community directed even a modicum of funding towards senescent cell clearance. There are lessons to be learned here, and one of them is that we could be closer to the defeat of aging than we are today had more people listened back then.

The first broad spectrum drug that can potently kill senescent cells in culture

Researchers are reporting the discovery of the first broad spectrum drug that can potently kill senescent (or aging) cells in culture and effectively clear the cells in animals by specifically targeting a pathway that is critical for the survival of senescent cells. Because senescent cells are believed to play a role in the late effects of radiation on normal tissues and certain age-related diseases, this study has broad implications for future therapies targeting the common biological mechanism that contributes to late tissue injury caused by radiation and aging. Cellular senescence, the loss of cells' ability to divide, normally functions as a tumor suppressive mechanism; however, senescent cells become "toxic" as they accumulate after exposure to radiation and with age. This is because they cause stem cell aging that reduces the ability of tissue regeneration and repair and drive chronic inflammation and oxidative stress. Since chronic inflammation and oxidative stress are thought to be the root cause of some late effects of radiation and many age-related diseases, including radiation-induced long-term bone marrow injury and age-related osteoarthritis and atherosclerosis, eliminating senescent cells has the potential to mitigate radiation-induced late tissue injury and treat many age-related diseases.

In the current study, ABT-263, a molecule initially developed as an anti-cancer therapy, was given orally to either normally aged mice or irradiated mice to induce premature aging of the hematopoietic system, the organs and tissues involved in production of blood. ABT-263 effectively depleted senescent cells, including senescent "stem cells" of the bone marrow and muscle. Depletion of the senescent cells appeared to reduce premature aging of the bone marrow caused by irradiation, and even rejuvenated the function of stem cells in normally aged mice. "Our results demonstrate that clearance of senescent cells by a pharmacological agent is beneficial in part by rejuvenating aged tissue stem cells. Because a decline in tissue stem cell function is associated with exposure to radiation and aging, we believe clearing senescent cells and rejuvenation of tissue stem cells could have a major impact on mitigation of radiation injury and treatment of diseases of aging. ABT-263 was originally developed as an anti-cancer agent. It has toxic side effects that make it inappropriate for development as an agent for diseases of aging. We are investigating next-generation small-molecule drugs that are optimized to clear senescent cells without drug-induced toxicity."

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice

Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug.

We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.