Tackling Cellular Senescence as a Treatment for Aging

The research community is now well and truly woken up when it comes to senescent cells and aging, after long years of ignoring this corner of the field, the paper linked below is illustrative of the sort of reviews on the subject being written nowadays. It took quite a while to achieve this awakening. Good evidence for senescent cell accumulation as a contributing cause of degenerative aging has existed for decades, and on the basis of that evidence clearance of senescent cells from old tissues was included in the SENS rejuvenation research proposals when they emerged at the turn of the century. Nonetheless, even as recently as five years ago researchers still struggled to raise the funds needed for the animal studies to prove the point. Once the first of those studies was completed, in 2011, things began to move, and now we have can observe an increasing pace of investment, development of practical therapies by numerous companies, and publication of new data on the biology of senescent cells. Life extension has been demonstrated in normal mice, and a recent studies demonstrate that removing senescent cells should help to slow or reverse the progression of specific age-related diseases and turn back numerous metrics of tissue aging. It is all very promising.

How do senescent cells cause harm? Largely through signaling, it appears, as they do not make up a large fraction of cells in any particular tissue even by the end of a natural life span. If even 1% of the cells in an aged tissue have become senescent, that is enough to cause significant issues. Senescent cells generate a mix of signal molecules that, in greater volume, can become very harmful; this is known as the senescence-associated secretory phenotype (SASP). It promotes chronic inflammation, alters the behavior of nearby cells for the worse, and can damage the structure of the extracellular matrix, among other issues. Why do we accumulate senescent cells? The phenomenon of senescence in old tissue appears to be an adaptation of an embryonic development process, now turned to cancer suppression. Indeed, much of its destructiveness makes more sense in the context of embryonic growth, where tissues must be removed or growth halted in order to correctly define organ structures. Cells become senescent at the Hayflick limit on division, or in response to damage or a toxic environment. In moderation this serves to reduce the risk of cancer by shutting down replication in the most vulnerable cells, those most likely to become cancerous. Levels of cellular damage and stress increase with aging, which will in turn increase the rate at which senescent cells arise. Further, senescent cells are largely destroyed either by the immune system or their own programmed cell death mechanisms. With advancing age, the immune system becomes ever more dysfunctional due to its own burden of damage, however, and thus less capable of removing senescent cells.

Therapeutic interventions for aging: the case of cellular senescence

Cellular senescence is a stress response characterized by the induction of a permanent cell cycle arrest. Senescence represents an important barrier to tumorigenesis by limiting the growth of potentially oncogenic cells. Senescence-associated growth arrest (SAGA) is accompanied by an overactive secretory phenotype known as the senescence-associated secretory phenotype (SASP). The SASP consists of numerous cytokines, growth factors, proteases and extracellular matrix components that, depending on the physiological context, can be either beneficial or deleterious. During early stages, SASP components promote the migration and infiltration of effector immune cells through the secretion of cytokines and facilitate tissue repair and remodeling by release of growth factors and proteases; however, in later stages, persistent senescent cells negatively impact the surrounding microenvironment by impairing tissue homeostasis through complex cell and non-cell autonomous effects.

In a cell-autonomous manner, selected SASP components such as interleukin (IL)-6 and IL-8 can reinforce SAGA through autocrine pathways. However, the same secreted components can act in paracrine signaling to neighboring cells, propagating the senescent phenotype and thus potentially hampering the regenerative capacity of surrounding tissue. Similarly, in a non-cell-autonomous manner, SASP cytokines promote infiltration of immune cells, yet persistent signaling can result in disruptive chronic inflammation, a hallmark of aging and major contributor to age-related dysfunctions. Indeed, senescent cells accumulate late in life and at sites of age-related pathologies, and genetic interventions enabling the effective clearance of senescent cells in genetically engineered animal models is sufficient to delay a number of age-related phenotypes.

Accordingly, a prolonged healthspan is obtained by pharmacological interventions using a novel class of drugs termed senolytics, used to selectively ablate senescent cells. Senolytic interventions not only demonstrated the feasibility of extending healthspan but also evidenced the alleviation of a wide range of pre-existent age-related symptoms including: improved cardiovascular function, reduced osteoporosis and frailty; enhanced adipogenesis, reduced lipotoxicity and increased insulin sensitivity; improved established vascular phenotypes associated with aging and chronic hypercholesterolemia; as well as radioprotection and rejuvenation of aged-tissue stem cells.

Although regeneration capacity deteriorates with age in mammals, it remains intact in other species such as salamanders. Surprisingly, salamanders show a significant induction of cellular senescence during limb regeneration; however, rapid and effective mechanisms of senescent cell clearance operate in regenerating tissues. Accordingly, the number of senescent cells does not increase upon aging, in contrast to mammals. However, very recently senescent cells have been shown to promote tissue regeneration also in mammals, probably through secretion of specific SASP factors. Thus, pharmacological or localized assisted immunological clearance of senescent cells might potentially aid regeneration of dysfunctional aged tissues.

The various beneficial effects resulting from the administration of drugs to selectively eliminate senescent cells, or suppress the deleterious aspects of the SASP, encourage their use in the treatment of age-related disabilities and chronic diseases as a group. Unfortunately, many challenges are still to be overcome for a successful drug development program, including increased selectivity and reduction of off-target effects. The optimization of therapeutic dosage in already approved drugs, now repurposed for aging interventions, appears promising in the reduction of unwanted side-effects, as demonstrated for rapamycin using lower intermittent doses. Additionally, the development of appropriate animal models capable of demonstrating the beneficial effects using clinically relative outcomes is imperative. These models would ideally be capable of distinguishing on-target from off-target effects to enable a correct assessment of safety and efficacy at a preclinical level, and ultimately grant their use in human clinical trials. In the near future, it is most likely that interventions against cellular senescence will only be prescribed on a case-by-case basis, for specific age-related dysfunctions, in patients with a favorable risk:benefit tradeoff; as is already the case in oncology where many identified senolytics are currently under investigation. Promisingly, however, human clinical trials are already underway to evaluate pharmaceutical impacts on longevity and human aging as a whole, extending our understanding on the human biology of aging and suggesting antiaging interventions could be closer than expected.

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