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, where cells cease to divide and therefore stop growing. It also leads to a decrease in the ability of progenitor cells to function. Progenitor cells are like stem cells in that they can self-renew and differentiate into different types of cells. In the heart, there are specific cardiac progenitor cells (CPCs) that have the ability to self-renew over a human lifespan.
In a paper published today in Aging Cell, authors show how they extensively examined the CPC’s isolated from human hearts, aged 32-86 years-of-age, with cardiovascular disease. They found that as a person ages, their CPC’s lose function and start to show impaired reparative potential and become ‘senescent’. They showed that approximately 50% of the CPC’s of humans aged 70 or over were senescent.
A characteristic of these aged-senescent CPC’s is that they secrete a substance known as ‘senescence-associated secretory phenotype’ (SASP), which can render neighbouring healthy cells to become senescent.
Recently, a new class of drugs, called senoltyics, are being developed. These drugs selectively identify senescent cells and force them to die, with the aim to delay, prevent, alleviate or reverse age-related diseases.
In this study, the authors treat a mixture of aged-senescent CPCs and non-senescent CPCs with senolytic drugs and find that the SASP effect is revoked.
They also demonstrated when treating geriatric aged mice with senolytics, it caused CPCs to divide and increase in number, and the formation of new cardiac contractile cells - cardiomyocytes. Therefore, therapeutic approaches that target senescent cells may alleviate cardiac deterioration with ageing and restore the regenerative capacity of the heart.
The findings demonstrate that 1) it may be feasible to isolate and grow CPCs even from older individuals that are functional and capable of supporting cardiac regeneration if removed from their toxic environment, and 2) by eliminating senescent cells with a toxic SASP from the aged heart, there remains a tissue-resident population of CPCs with reparative potential. Both approaches could be therapeutically relevant in treating patients.
Stem cell therapy for cardiac repair holds great promise, but our findings show that the ability of CPCs to repair damaged myocardium declines with age. However, eliminating aged-senescent cells with senolytic drugs appears to rejuvenate the heart’s reparative potential, which is really exciting.”– Dr Georgina Ellison-Hughes, Centre for Human & Applied Physiological Sciences, School of Basic & Medical Biosciences
The next steps in this research are to determine the mechanism of action of senolytics on improving the reparative capacity of the heart.
This research was a collaboration with Professor James Kirkland and Dr Tamara Tchkonia at the Mayo Clinic, USA and supported by funding from the BHF and NIH.
Read the paper here.