Senotherapeutic agents: Advances and perspectives

23 - 09 - 2021

Aging is accompanied by tissue degeneration. Cellular senescence is at the origin of many degenerative processes. All cells can be affected, but certain tissues/organs are more sensitive, starting with the cardiovascular system, which is the first to be affected.

Senescent cells are characterised by an intracellular accumulation of damaged biomolecules and organelles, affecting cell function. Many dysfunctional mitochondria – one of the markers of senescence – participate in increased cellular oxidative stress and lead to metabolic aberrations. If not eliminated, senescent cells eventually spread their phenotype to surrounding tissues through their specific secretory profile.

As we age, stem cells – cells capable of renewing senescent cells in our tissues – become less and less active. The same applies to the immune system, which is less and less able to defend the body effectively.

Immunosenescence results in a marked loss of effectiveness of both innate and acquired responses, which contributes to the diminished immune responses of the elderly. This reduces theimmune clearance of senescent cells. Senescent cells, which eventually accumulate, then favour the secretion of pro-inflammatory factors and the development of diseases (e.g. degenerative pathologies, chronic inflammatory diseases, cancers, etc.).

Fortunately, the elimination of senescent cells or their neutralisation protects against age-related diseases. Eliminating or blocking the action of these cells with so-called senotherapeutic agents can prevent tissue degeneration and improve healthy life expectancy. Three main categories of senotherapeutic agents, of natural or synthetic origin, are to be considered: senosuppressants, senostatics and senolytics. By blocking the action and/or pathways responsible for the production of pro-senescent factors, senosuppressive agents can prevent senescence and are therefore part of preventive strategies. Senostatic and senolytic agents (e.g. fisetin, dasatinib/quercetin, etc.) are indicated to treat senescent cells already present in a pathological tissue, the former by blocking or even reversing the intracellular mechanisms promoting senescence, the latter by selectively eliminating senescent cells from a tissue or organ. By extension, the term senolytic has been extended to any substance that can reduce the deleterious effects induced by the presence of senescent cells.

By reducing the number of senescent cells and thereby slowing down ageing, senolytic compounds are a promising anti-ageing strategy with major therapeutic prospects. Their ability to be used as adjuvants to chemotherapies is also of great interest.

Disclaimer : This information is provided for guidance only and is not a substitute for medical advice.

 

References:

Veret D, Brondello JM. Senotherapy: Advances and new clinical perspectives. Med Sci (Paris). 2020;36(12):1135-1142.

He S, Sharpless NE. Senescence in health and disease. Cell 2017;169(6):1000-1011.

Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med 2018; 24(8):1245-1256.

Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 2018; 36:18-28.

Ovadya Y, Landsberger T, Leins H, et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun 2018: 9(1):5435.

Jeon OH, Kim C, Laberge R-M, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23(6):775-781.

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