Senolytics: Can we treat age-related diseases with a single drug

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Can we treat age-related diseases with a single drug?

The increasing life expectancy of the world population has become an economic and global public health problem. Increased life expectancy tracks with a higher incidence of multiple chronic conditions, despite unprecedented advances in prevention, diagnostics, and treatment. Ageing is the greatest risk factor for many life-threatening disorders, including cardiovascular disease, neurodegeneration and cancer.

Ageing leads to an increase in a phenomenon known as cellular senescence in several tissues, including the heart. Senescent cells can no longer grow and repair damaged tissues and with increasing age they build up in our bodies and refuse to die. The main problem is that senescent cells release pro-inflammatory chemicals that can be harmful to nearby cells, damage surrounding tissues and eventually cause disease. Research has shown that the build-up of senescent cells in the body promotes ageing and the conditions that come with it like osteoporosis, Alzheimer’s disease and cardiovascular disease (Roos et al., 2016; Farr et al., 2017; Ogrodnik et al., 2019; Anderson et al., 2019).

Senolytics – a new class of drugs to treat age-related disease

A new class of agents have been developed which eliminate or induce death to senescent cells named ‘senolytics’ - from the words “senescence” and “lytic” – destroying. Recent pre-clinical studies conducted in mice have shown senolytics clear or eliminate senescent cells from ‘aged’ tissues resulting in delaying, preventing or alleviating multiple age- and senescence-related conditions, including frailty, cataracts, age-related osteoporosis, age-related loss of muscle, radiation-induced damage, cardiac dysfunction, vascular dysfunction and calcification, pulmonary fibrosis, hepatic steatosis, metabolic syndrome, diabetes and dementia (Kirkland et al., 2017; Kirkland & Tchkonia, 2017; Tchkonia & Kirkland, 2018). Overall, administration of senolytic agents and elimination of senescent cells have shown to improve physical function and extend health span and lifespan (Xu et al., 2018).

Classes of senolytics

Senolytics thus far tested include dasatinib (D, a US Food and Drug Administration [FDA] approved tyrosine kinase inhibitor), quercetin (Q, a flavonoid present in many fruits and vegetables), navitoclax, A1331852 and A1155463 (Bcl-2 pro-survival family inhibitors) and fistein (like Q, a flavonoid), geldanamycin, alvespimycin and tanespimycin (HSP-90 inhibitors) piperlongumine and a FOXO4-related peptide.

Clinical application of senolytics

A handful of clinical trials of senolytics are underway. Some are phase I or II trials using repurposed drugs approved by the FDA for other indications or natural products for participants with symptomatic senescence-associated disorders, such as chemotherapy-induced physical dysfunction. The results of the first clinical trial of senolytics have just been published. Subjects with idiopathic pulmonary fibrosis showed enhanced walking endurance, gait speed, chair rise test performance, and scores in the Short Physical Performance Battery 5 days after 9 doses of D+Q over 3 weeks (Patience et al., 2019). However, until the clinical trials have proved safe, patients should be advised not to self-medicate with senolytic agents or other drugs that target fundamental aging processes in the expectation that conditions alleviated in mice will be alleviated in people.

If senolytic drugs are effective across a range of disorders, provided they are safe, clinical trials of senolytics might move toward studies in pre-symptomatic individuals to delay or prevent age-related conditions. Professor James Kirkland and his team at the Mayo Clinic’s Robert and Arlene Kogod Center on Aging have recently been awarded funding for a Translational Geroscience Network, which will design and conduct clinical trials targeting fundamental aging mechanisms to extend health span and delay, prevent, or treat age- and cellular senescence-related conditions.

Senolytics represent a new potential treatment approach, but the adverse effects of these therapies remain to be fully elucidated. If senolytics are shown to be safe and effective in humans, they could transform care of older adults and patients with multiple chronic diseases that now can only be managed and have not been amenable to disease modifying interventions.

References:  

Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019;38:e100492. doi: 10.15252/embj.2018100492

Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL et al. Targeting cellular senescence prevents age-related bone loss in mice. ; Nat Med. 2017;23:1072-1079. doi: 10.1038/nm.4385.

Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554-563.

Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD. The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc. 2017;65:2297-2301. doi: 10.1111/jgs.14969.

Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017;21:21-28. doi: 10.1016/j.ebiom.2017.04.013.

Ogrodnik M, Zhu Y, Langhi LGP, Tchkonia T, Krüger P, Fielder E et al. Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis. Cell Metab. 2019;29:1233. doi: 10.1016/j.cmet.2019.01.013

Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15:973-977. doi: 10.1111/acel.12458.

Tchkonia T, Kirkland JL. Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies. JAMA. 2018;320:1319-1320. doi: 10.1001/jama.2018.12440.

Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK., Weivoda MM et al. Senolytics improve physical function and increase lifespan in old age. Nature Medicine. 2018;24:1246-1256. doi:10.1038/s41591-018-0092-9

Author: Georgina Ellison-Hughes, PhD- Professor of Regenerative Muscle Physiology

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I am Professor of Regenerative Muscle Physiology in the School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King’s College London, UK. My research focuses on understanding the role of tissue-specific stem/progenitor cells in the homeostasis and regeneration of striated (skeletal and cardiac) muscle, for repair and maintenance of muscle tissue, particularly preventing and treating a loss of muscle mass (i.e. with ageing and/or disease). The findings are directly transferrable to the treatment of cardiovascular disease/failure, muscular dystrophy, muscle wasting and age-related diseases. My efforts have been at the forefront of pioneering research on adult-derived cardiac stem/progenitor cells and have made a seminal contribution in the paradigm shifting work to establish the adult heart as a self-renewing organ with regenerative capacity.

I have received funding from the Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust, British Heart Foundation (BHF), Heart Research UK, King’s Health Partners, European Commission and American Heart Association. I have made highly impactful contributions to the field establishing a world-leading track record with publications in top journals, such as Cell, Journal of the American College of Cardiology, European Heart Journal, Circulation Research, Nature Protocols, Aging Cell.

I am Associate Editor of Scientific Reports, BMC Molecular and Cell Biology, Frontiers Pharmacology. I was recipient of a Scholarship for academic excellence from the British Federation of Women Graduates (2003) and the Young Investigator of the Year (2005) at the European College of Sports Sciences (ECSS). I was recognised as one of Best of British Early Career Researchers at the House of Commons (2007).