Fight Aging!

Today's open access paper is a very readable tour of the present state of research and development of therapies targeting senescent cells, whether to destroy them or alter their function in favorable ways. In both cases the primary goal is to reduce the senescence-associated secretory phenotype (SASP), the pro-growth, pro-inflammatory signaling that contributes to degenerative aging as the number of senescent cells rises over the course of later life. It is hoped that clearance of senescent cells will produce a sizable positive impact for late life health, reducing chronic inflammation, slowing the onset of near all age-related conditions, and even reversing existing pathology. The animal studies are impressive when it comes to that last point.

Senescent cells are a good example of antagonistic pleiotropy. The transient presence of senescent cells and SASP is selected for because it is useful during embryonic development, and continues to provide benefits in early life, such as assisting in wound healing, and reducing cancer incidence. When senescent cells cannot be cleared efficiently in later life, and they linger, then they become harmful. Natural selection tends to produce situations of this nature, as selection pressure is strongest in early reproductive live span. It allows for the generation of systems and mechanisms that fall apart over time or otherwise become pathological in an aged body.

Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging

To date, a handful of senolytics have been examined in a variety of preclinical models. In naturally aged mice and atherosclerosis mouse models, the dasatinib and quercetin ("D + Q") administration improved cardiac function. In radiation-damaged mice, "D + Q" enhanced exercise capacity. In osteoporosis mouse models, administration of "D + Q" increased bone mass and strength, providing a novel treatment strategy for not only osteoporosis but multiple age-related comorbidities. Adipose tissue inflammation and dysfunction are causative for obesity-related diabetes and insulin resistance, but "D + Q" alleviated metabolic and adipose tissue dysfunction in obese mice, suggesting the potential of senolytics in treating obesity-related metabolic dysfunction and complications.

Senolytic agents have exhibited substantial efficacy in delaying, preventing or alleviating physical frailty, multiple cancers, and a variety of cardiovascular, liver, kidney, musculoskeletal, lung, eye, hematological, metabolic, and neuropsychiatric pathologies as well as complications of cancer treatment and organ transplantation. Through targeting fundamental aging mechanisms, which are considered as "root cause" contributors to multiple chronic disorders, senolytics hold the potential to alleviate over 40 or even more age-related conditions as illustrated by preclinical studies, thus opening a new avenue for treatment of age-related dysfunction and chronic pathologies.

So far, mounting lines of evidence support the efficacy of senescence-targeting agents, namely senotherapeutics, which mainly comprise senomorphics and senolytics. Early preclinical data about senolytics, small molecule agents that eradicate senescent cells, have shown promising indications of effectiveness across several aging and disease models. The first wave of in-human trials with the senolytic combination of "D + Q" suggested decreased senescent cell burden in adipose tissue of patients with diabetic kidney disease and improved physical function in patients with idiopathic pulmonary fibrosis (IPF). Clinical trials with other senolytics, including the flavonoid fisetin and Bcl-xL inhibitors, are currently in progress.

The first clinical trial of senolytics demonstrated improved physical function in IPF patients after "D + Q" administration in a first-in-human, open-label, and pilot study, warranting evaluation of "D + Q" in expanded randomized controlled trials for senescence-related disorders. Similarly, another pilot clinical trial reported that treatment with "D + Q" reduces senescent cell burden in adipose tissues of patients developing diabetic kidney disease. Specifically, adipose tissue activated macrophages and adipose tissue fibrosis were decreased, as were levels of circulating SASP factors, including IL-1α, IL-6, and matrix metalloproteinases (MMPs), confirming target engagement (senescent cell decreases) using a "hit-and-run" treatment strategy with senolytics.

More recently, an open-label early phase 1 trial of "D + Q" for Alzheimer's disease (SToMP-AD) reported that intermittent senolytic administration decreases tau protein accumulation and neuro-inflammation, preserves neuronal and synaptic density, partly restores cerebral blood flow and reduces ventricular enlargement. The results support the initiation of a randomized, double-blind and placebo-controlled multicenter phase II trial, which aims to further explore the safety, feasibility, and efficacy of senolytics in treating Alzheimer's disease.