Senotherapeutics are a new class of drugs designed to combat one of the key mechanisms of aging – the accumulation of senescent cells. These cells, although they do not divide, remain metabolically active and secrete a range of pro-inflammatory factors that disrupt tissue function and contribute to age-related diseases such as atherosclerosis, osteoporosis and neurodegenerative diseases. Understanding how to eliminate these cells or modify their activity can significantly improve tissue health and delay the aging process..
Mechanism of action of aging cells
Senescent cells are caused by various stress factors, such as DNA damage, telomere shortening, and oxidative stress. At the molecular level, activation of signaling pathways, such as p16^INK4a^ and p21, causes cell cycle arrest. In this phase, these cells enter a state of senescence, but are not eliminated by natural mechanisms, which causes their accumulation in tissues. Senescent cells are characterized by the so-called SASP phenotype (Senescence-Associated Secretory Phenotype), which includes the secretion of proinflammatory cytokines, chemokines, and enzymes that degrade the extracellular matrix.
The Role of Senescent Cells in Age-Related Diseases
- Atherosclerosis: Accumulation of senescent cells in blood vessel walls leads to endothelial dysfunction and chronic inflammation, which accelerates the development of atherosclerosis.
- Osteoporosis: Aging osteocytes reduce osteoblast activity, which weakens bone structure, increasing the risk of fractures.
- Neurodegenerative diseases: In the brain, aging glial cells, such as microglia and astrocytes, contribute to increased inflammation, which is associated with the progression of Alzheimer's disease.
- Tissue fibrosis: Aging fibroblasts may contribute to pathological collagen deposition, leading to fibrosis of the lungs, liver, and kidneys.
Senotherapeutics: A New Approach to Anti-Aging Therapies
Senotherapeutics are divided into two main groups:
- Senolytics: Drugs that selectively eliminate senescent cells by inducing their apoptosis. Examples include dasatinib, quercetin, fisetin, and navitoclax. Senolytics work by inducing cellular stress in senescent cells, which leads to their death.
- Senostatics: Substances that reduce SASP secretion without eliminating senescent cells. Examples include metformin and rapamycin, which inhibit mTOR pathway activity, reducing tissue inflammation.
Overview of the most important senotherapeutics and their potential
- Dasatinib and Quercetin: The combination of these two senolytics was effective in eliminating senescent cells in models of lung fibrosis and osteoporosis, improving tissue health.
- Fisetin: A natural flavonoid found in fruits that has potent senolytic effects, reduces inflammation and improves metabolic health.
- Navitoclax: An inhibitor of BCL-2 family proteins that eliminates senescent cells in models of neurodegenerative diseases.
- Gingerenone A: Active ingredient isolated from ginger that reduces the viability of senescent cells by activating caspase-3 and reducing the expression of pro-survival proteins.
Results of clinical trials on senotherapeutics
Clinical trials of dasatinib and quercetin in the treatment of idiopathic pulmonary fibrosis have shown improved respiratory function and reduced tissue inflammation. Animal studies have shown that eliminating senescent cells improves tissue health, delays the aging process and extends lifespan.
Senotherapeutics in Clinical Practice: Challenges and Future Applications
The biggest challenge in using senotherapeutics is ensuring their selectivity and safety. Senolytics can lead to the elimination of healthy progenitor cells, which affects the ability of tissues to regenerate. Personalization of therapy, taking into account specific pathologies and types of tissues affected by aging, may prove to be the future of senotherapy..
Future directions of research on senotherapeutics
Future research will focus on:
- Identification of new senolytics: Search for compounds with greater selectivity and less toxicity.
- Combined therapies: Studies on the synergistic effects of senotherapeutics with other anti-aging interventions such as diet, intermittent fasting or epigenetic modulators.
- In vitro and in vivo modeling: Application of advanced animal models and organoids to study the efficacy and safety of new senotherapeutics.
Senotherapeutics represent a promising strategy in the fight against age-related diseases. Their ability to selectively eliminate senescent cells or modulate their activity could be key in future anti-aging therapies. However, more research is still needed to better understand their effects on the body and determine the optimal way to use them..
Sources:
- Identification of gingerenone A as a novel senolytic compound
- A proteomic atlas of senescence-associated secretomes for aging biomarker development
- A new aging measure captures morbidity and mortality risk across diverse subpopulations from NHANES IV: A cohort study