6 Anti-Aging Drugs with Senolytic Properties to Promote Longevity

Senolytics and senomorphics represent a promising new drug category that targets the aging process’s underlying causes. These innovative medications are designed to target “bad” cells that appear during aging by either eliminating them or reducing the production of harmful molecules that they produce.

While we age, cells in our body gradually stop replicating and go into the silent state of senescence, which is one of the hallmarks of aging. These bad cells are called senescent cells. Although senescent cells are not dividing, they are metabolically active and secrete different proteins and molecules that cause constant inflammation in surrounding tissues and organs. This phenomenon is called senescence-associated secretory phenotype (SASP). Overall, senescence is associated with a decline in physical and cognitive function and increased susceptibility to disease and death. ¹ Childs, Bennett G et al. “Cellular senescence in aging and age-related disease: from mechanisms to therapy.” Nature medicine vol. 21,12 (2015): 1424-35.PubMed Source

During the last decade, researchers have been actively studying the biological mechanisms underlying senescence and molecules/drugs that can affect this process. They identified some natural and synthesized components that selectively kill senescent cells (senolytics) or suppress their secretory phenotype (senomorphics).² Niedernhofer, Laura J, and Paul D Robbins. “Senotherapeutics for healthy ageing.” Nature reviews. Drug discovery vol. 17,5 (2018): 377. PubMed Source

BCL-2 is a family of proteins that are important for cell survival that confers senescent cell resistance to apoptosis. Therefore, the inhibitors of these proteins induce apoptotic cell death of senescent cells.

BCL-2 inhibitors include different molecules. The most extensively studied are ABT-737, ABT-263 (Navitoclax), A-1331852, and A-1155463. In animal studies, these drugs rejuvenate aged stem cells and kill senescent cells.⁸ Yosef, Reut et al. “Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL.” Nature communications vol. 7 11190. 6 Apr. 2016. PubMed Source

So far, in clinical studies, BCL-xL inhibitors have improved visual acuity in patients with macular degeneration. However, many BCL-2 inhibitors have severe adverse effects, which will limit their clinical use.

Rapamycin is a potent senomorphic agent. It reduces cellular senescence and suppresses SASP markers. Initially, rapamycin was used as an anti-fungal agent. Later, its immunosuppressive and anti-proliferative properties were discovered, and FDA approved it as a preventive drug during organ transplantation and for treating certain types of cancer.

The science behind rapamycin life extension properties is very strong. It prolongs the lifespan of all studied organisms, including yeast, worms, flies, and mice.⁹ Selvarani, Ramasamy et al. “Effect of rapamycin on aging and age-related diseases-past and future.” GeroScience vol. 43,3 (2021): 1135-1158. PubMed Source The life-extension properties of rapamycin are attributed to its ability to inhibit the activity of mTOR, a key pathway associated with aging.

Rapamycin use was reported safe in clinical trials of healthy, aged people.¹⁰ Kraig, Ellen et al. “A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.” Experimental gerontology vol. 105 (2018): 53-69. PubMed Source However, its life extension properties are still to be studied. Rapamycin has some side effects, including metabolic dysregulation, thrombocytopenia, hyperlipidemia, and impaired wound healing.¹¹ Li, Jing et al. “Rapamycin: one drug, many effects.” Cell metabolism vol. 19,3 (2014): 373-9 PubMed Source. So, the benefits and risks should be weighed before considering rapamycin for life extension purposes in the general public.

Metformin is a first-line drug that is originally FDA-approved for the treatment of type 2 diabetes. Nowadays, its use has extended to age-related disorders, including insulin resistance, obesity, liver diseases, cardiovascular diseases, and cancer. Metformin suppresses cellular senescence reducing age-associated impairments, which makes it a strong agent with senomorphic properties.

Metformin increases health span and lifespan in different organisms, including worms and mice, independent of its effect on diabetes.¹² De Haes, Wouter et al. “Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2.” Proceedings of the National Academy of Sciences of the United States of America vol. 111,24 (2014): E2501-9. PubMed Source ¹³ Martin-Montalvo, Alejandro et al. “Metformin improves healthspan and lifespan in mice.” Nature communications vol. 4 (2013): 2192. PubMed Source

Studies have shown that people with diabetes who take metformin have a lower risk of age-related diseases and death than those without diabetes who don’t take it.¹⁴ Bannister, C A et al. “Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls.” Diabetes, obesity & metabolism vol. 16,11 (2014): 1165-73. PubMed Source This led to the speculation that people with diabetes might live longer than healthy individuals.

Preliminary results of using metformin from clinical trials on non-diabetic patients showed promising results.¹⁵ ClinicalTrilas.gov Effects of Metformin in a Non-Diabetic Patient Population Source That’s why nowadays, metformin is under clinical trials as the initial step of developing next-generation drugs targeting aging in healthy individuals.

Statins are drugs that are classically used for lowering cholesterol levels in the blood of patients with hypercholesterolemia. Some statins (atorvastatin, pravastatin, and pitavastatin) can lower the SASP effect and suppress SASP-induced cancer.¹⁶ Ota, Hidetaka et al. “Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway.” Arteriosclerosis, thrombosis, and vascular biology vol. 30,11 (2010): 2205-11. PubMed Source ¹⁷ Liu, Su et al. “Simvastatin suppresses breast cancer cell proliferation induced by senescent cells.” Scientific reports vol. 5 17895. 14 Dec. 2015. PubMed Source

However, statins have strong side effects, including muscle problems, increased risk of type 2 diabetes, and liver damage. So, their use in combating aging in healthy people is questionable. And further research is needed to fully understand the potential benefits and risks of using statins as an anti-aging therapy.

Aspirin is a widely-used non-steroidal anti-inflammatory drug, often used to treat many age-related diseases such as atherosclerosis, arthritis, osteoporosis, and cancer. Aspirin is well-known for reducing the risk of heart attack or stroke but can also reduce the risk of certain cancers (such as colon cancer).¹⁸ Hybiak, Jolanta et al. “Aspirin and its pleiotropic application.” European journal of pharmacology vol. 866 (2020): 172762. PubMed Source

With regard to its anti-aging properties, in animal models, it has been shown that aspirin can extend its lifespan.¹⁹ Lushchak, Oleh et al. “Aspirin as a Potential Geroprotector: Experimental Data and Clinical Evidence.” Advances in experimental medicine and biology vol. 1286 (2021): 145-161. PubMed Source Aspirin also suppresses cellular senescence.²⁰ Feng M, Kim J, Field K, Reid C, Chatzistamou I, Shim M. Aspirin ameliorates the long-term adverse effects of doxorubicin through suppression of cellular senescence. FASEB Bioadv. 2019 Sep 9;1(9):579-590. doi: 10.1096/fba.2019-00041. PMID: 32123852; PMCID: PMC6996307. PubMed Source

With regards to its anti-aging properties, in animal models, it has been shown that aspirin can extend its lifespan and suppress senescence.²¹ Lushchak, Oleh et al. “Aspirin as a Potential Geroprotector: Experimental Data and Clinical Evidence.” Advances in experimental medicine and biology vol. 1286 (2021): 145-161. PubMed Source ²² Feng M, Kim J, Field K, Reid C, Chatzistamou I, Shim M. Aspirin ameliorates the long-term adverse effects of doxorubicin through suppression of cellular senescence. FASEB Bioadv. 2019 Sep 9;1(9):579-590. doi: 10.1096/fba.2019-00041. PMID: 32123852; PMCID: PMC6996307. PubMed Source

However, while these studies suggest that aspirin may have potential anti-aging effects, it’s important to note that further research is needed to fully understand the risks and benefits of using aspirin as an anti-aging therapy Aspirin, as any other medicine, has side effects and can induce excessive bleeding, so a medical professional should guide its long-term use.