Senolytics: an emerging therapeutic for the prevention and treatment of cardiovascular disease

Welcome to the first in a two-part introduction and discussion about senolytics 

Senolytics are small molecules under basic research to determine if they can selectively induce death of senescent cells (damaged cells that do not die but persist and become toxic to the cells around them). Cellular senescence has been shown to drive multiple age-related diseases, including idiopathic pulmonary fibrosis (IPF), a chronic, irreversible and progressive disease that results in scarring of the lungs.

Research goals for senolytics are to develop agents to delay, prevent, alleviate, or reverse age-related diseases.

Age-related cardiovascular disease

Age-related cardiovascular disease (CVD), including chronic heart failure, hypertension and coronary artery disease (CAD, atherosclerosis), are expected to affect over one billion people over the age of 65 by 2030. Recent British Heart Foundation (BHF) statistics reveal that CVD is a growing global burden with heart, stroke and artery disease deaths all rising for the first time in 50 years. There has been a shift away from prevalence of lipid rich atheroma, due to effective treatments with lipid lowering drugs, towards new emerging pathologies that are associated with ageing such as Heart Failure preserved Ejection Fraction (HFpEF), arterial stiffening, resistant hypertension and dementia. Aging is associated with complex structural and functional changes in the vasculature independently of other risk factors, such as hypertension, diabetes, or hypercholesterolemia. Vascular hyporeactivity is associated with vascular stiffness, and calcification of the aorta, which are drivers for stroke, atrial fibrillation and dementia. The risk of dying from a heart attack increases by 6% each year once over the age of 70. HFpEF is a disease of the older population; as the population continues to age, HFpEF prevalence increases at a rate of over 10% per decade.  

Senescent cells accumulate in the aging cardiovascular system and drive age-related CVD

Senescent cells are damaged cells that no longer function properly but remain in the body and contribute to frailty and many other health conditions associated with aging. Pre-clinical studies show that senescent cell accumulation contributes to age-related cardiac dysfunction, vascular dysfunction and calcification, and impaired cardiac repair. Although senescent cells accumulate with aging (primary senescent cells), secondary senescent cells arise in comparably large numbers as a result of cellular stressors. For example, children on dialysis develop medial vascular calcification and exhibit ‘premature ageing’ with accumulation of large numbers of senescent cells in their blood vessels (Sanchis et al., 2019).

Senolytics – a new class of drugs that clear senescent cells

In pre-clinical studies, elimination or clearance of senescent cells, using short-term treatment of a new class of drugs named senolytics, have shown to improve physical function and extend health span and lifespan (Xu et al., 2018). 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 (Kirkland et al., 2017; Kirkland & Tchkonia, 2017; Tchkonia & Kirkland, 2018). 

Senolytic treatment improves cardiac and vascular function

The contractile cells of the heart, the cardiomyocytes, acquire a senescent-like phenotype and increase in size (become hypertrophic) with increasing age. Aged mice show an increased mean left ventricular mass indicative of hypertrophy and increased ventricle wall rigidity, symptomatic of a decline in diastolic function, both of which are characteristics of HFpEF patients. Pharmacological elimination of senescent cells using senoltyic navitoclax or D+Q administration in aged, geriatric mice did not adversely alter cardiac function, but alleviated detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis, and induced a compensatory cardiomyocyte renewal and replacement (Anderson et al., 2019).

In the heart, including human heart, there are specific cardiac progenitor cells (CPCs) that have the ability to self-renew over a human lifespan and replace cells such as cardiomyocytes and vascular cells lost due to damage. Increased age leads to increased number of impaired, senescent cardiac progenitor cells which are unable to participate in repairing the heart following damage, such as a heart attack. Approximately 50% of the CPC’s in the human heart of a subject aged 70 or over are senescent. When treating geriatric aged mice with D+Q senolytics, it caused CPCs to divide and increase in number, leading to the formation of new cardiomyocytes (Lewis-McDougall et al., 2019). Therefore, eliminating senescent cells with senolytic drugs appears to rejuvenate the heart’s reparative potential.

Senescent cells contribute to the poor prognosis and survival of aged individuals following heart attack or myocardial infarction (MI). Aged mice have significantly higher mortality rates following MI (60% over 5 weeks post-MI), and showed a significant reduction in cardiac function between 1 and 4 weeks post-MI, compared with young mice. This functional decline was rescued by prior clearance of senescent cells by navitoclax treatment in aged mice (Walaszczyk et al., 2019).

Senescent cells accumulate in the blood vessels with age contributing to impaired vascular function and calcification. Chronic senolytic treatment with D+Q alleviated vasomotor dysfunction and plaque calcification in naturally aging mice and mice with established atherosclerosis, respectively (Roos et al. 2016). 

Research on senolytics is rapidly gaining ground and clinical trials on senolytics are already underway (Justice et al., 2019). In the near future, it is likely that the use of senolytics to remove senescent cells in humans may be an effective complementary therapy to classical risk factor management to reduce morbidity and mortality associated with age-related CVD.

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.
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.
Lewis-McDougall FC, Ruchaya PJ, Domenjo-Vila E, Shin Teoh T, Prata L, Cottle BJ et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 2019;18:e12931. doi: 10.1111/acel.12931.
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.
Sanchis P, Ho CY, Liu Y, Beltran LE, Ahmad S, Jacob AP et al. Arterial "inflammaging" drives vascular calcification in children on dialysis. Kidney Int. 2019;95:958-972. doi: 10.1016/j.kint.2018.12.014.
Tchkonia T, Kirkland JL. Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies. JAMA. 2018;320:1319-1320. doi: 10.1001/jama.2018.12440. 
Walaszczyk A, Dookun E, Redgrave R, Tual-Chalot S, Victorelli S, Spyridopoulos I et al. Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Aging Cell. 2019;18:e12945. doi: 10.1111/acel.12945.
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

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).

Part 2: Can we treat age-related diseases with a single drug can be found here.