Fight Aging!

This short open access review paper covers some of the high points of the past decade of development of senolytic therapies capable of selectively destroying senescent cells in old tissues, as well as some of the earlier, much more sparse work on cellular senescence, prior to the general acceptance of an important role for senescent cells in aging. Senescent cells are constantly created and destroyed in the body. They are beneficial when present in the short term, acting to coordinate wound healing and in suppression of potentially cancerous cells, for example. Near all are destroyed soon after their creation, via programmed cell death or the activity of the immune system. A lingering population of senescent cells grows in number with age, however, as the processes of clearance falter and the tissue environment becomes more damaged. The mix of signals that these cells generate, the senescence-associated secretory phenotype, causes chronic inflammation and disruption of tissue structure and function, contributing to the progression of age-related disease and mortality.

Aging is defined as a progressive decrease in physiological function accompanied by a steady increase in mortality. The antagonistic pleiotropy theory proposes that aging is largely due to the natural selection of genes and pathways that increase fitness and decrease mortality early in life but contribute to deleterious effects and pathologies later in life. Cellular senescence is one such mechanism, which results in a permanent cell cycle arrest that has been described as a mechanism to limit cancer cell growth. However, recent studies have also suggested a dark side of senescence in which a build-up of senescent cells with age leads to increased inflammation due to a senescence-associated secretory phenotype (SASP). This phenotype that includes many cytokines promotes tumorigenesis and can exhaust the pool of immune cells in the body.

In a 2006 primate study, it was observed that senescent cells, as estimated by ATM activation do accumulate and can reach over 15% of the total cell population in aged individuals. In contrast to the vast majority of in vitro studies, this was one of the first studies showing a clear association between aging and the accumulation of senescent cells in vivo. Although this established a strong correlation, efforts were underway to establish causation between the accumulation of senescent cells and aging in vivo. In 2011, the researchers showed that removing p16Ink4a positive senescent cells delayed age-related disorders and increased healthspan in a BubR1 progeroid accelerated model of aging mice. Later studies confirmed the beneficial effects of senescent cell removal in wild type mice that showed increased median lifespan, delayed tumorigenesis, and attenuated age-related multi-organ deterioration. Removal of senescent cells in mice has also been shown to attenuate markers of age-associated neurodegenerative diseases such as tau hyperphosphorylation and neurofibrillary tangle deposition.

Substantial evidence in the last decade connecting senescent cell accumulation, age-related ailments, and roles in lifespan and healthspan fueled the search for therapeutic compounds that could selectively target senescent cells. A transcriptomic analysis between senescent cells and proliferating cells showed increased expression of pro-survival/anti-apoptotic genes such as Bcl-xL, a member of the Bcl-2 family of proteins that regulates programmed cell death by blocking caspase activation. This provided evidence to support the observation that senescent cells accumulate with age by being resistant to a variety of stresses that would normally induce apoptosis. Consistent with this idea, siRNAs to reduce Bcl-xL expression selectively reduced survival and viability in senescent cells while not affecting proliferating cells. Quercetin and dasatinib were obtained as hits from a drug screen based on these observations.

These compounds form one of the first discovered members of the senolytic class of drugs that selectively induce apoptosis in senescent cells. Four years after their initial identification as candidate senolytics, a dasatinib and quercetin combination was reported to decrease the senescent cell burden in humans as part of a Phase-1 clinical trial in diabetic kidney disease patients. This 2019 study was the first peer-reviewed study to demonstrate the efficacy of senolytics to decrease senescent cell burden in humans. This was carried out after an initial pilot study in early 2019 in 14 idiopathic pulmonary fibrosis (IPF) patients was completed to evaluate the feasibility of implementing a senolytic treatment. What now remains to be determined is whether future clinical trials will demonstrate any positive medical outcomes resulting from decreased senescent cell burden in diabetes and other age-associated ailments.

Link: https://doi.org/10.3389/fcell.2019.00367