The "longevity medicine" that directly hits senescent cells How far are we from success?

Aging refers to the process in which the body's physiological functions gradually decline with age

Senescent cells are an important driver of individual aging

Biomarkers and therapeutic strategies of senescent cells

The accumulation of senescent cells is considered to be the underlying mechanism underlying the occurrence of senescence

The paper points out that cell cycle arrest is a prerequisite for senescence, and senescent cell cycle arrest signals are mainly located in the p53/p21 and RB/p16 pathways

Interestingly, in addition to cell growth arrest, another important feature of cellular senescence is the development of a senescence-associated secretory phenotype (SASP)

Based on the mechanism of action of senescent cells, the current therapeutic strategies to eliminate senescent cells are mainly divided into two categories:

The first category: selective killing of senescent cells, known as "Senolytic therapy";

The second category: Eliminate the production and secretion of SASP in senescent cells, which is called "Senomorphic therapy"

Since Senomorphic therapy "treats the symptoms but not the root cause" and usually requires long-term continuous administration, the "Senolytic therapy" that directly targets senescent cells has high hopes

The paper focuses on the latest exploration of "Senolytic therapy", such as Src kinase inhibitor + flavonoid combination, such as dasatinib + quercetin combination (D+Q); BCL-2 family protein inhibitors are summarized

The latest research progress of anti-aging cell drugs

The first published clinical study of Senolytic therapy was an open-label pilot trial of 14 patients with idiopathic pulmonary fibrosis (NCT02874989) who received 9 doses of dasatinib and quercetin over a 3-week period The combination (D+Q) was administered orally

In addition, a recent phase I, open-label clinical trial evaluating D+Q in patients with diabetic nephropathy (NCT02848131) reported interim results

Several other clinical trials are also ongoing or about to begin, including:

D+Q regimen for Alzheimer's disease (ALSENLITE, NCT04785300; SToMP-AD, NCT04685590), accelerated aging symptoms in bone marrow transplant patients (HTSS, NCT02652052), accelerated aging symptoms in children with tumor (SENSURV, NCT04733534), age-related bone marrow Porosis (NCT04313634), etc.

Fisetin in elderly women with debilitating symptoms (AFFIRM, NCT03430037), diabetes and chronic kidney disease (NCT03325322), children with oncology (compared to the D+Q regimen in the SENSURV trial), age-related osteoporosis (compared to D in NCT04313634) +Q program), osteoarthritis (NCT04210986), etc.

The Bcl-xL inhibitor UBX1325 in the treatment of diabetic macular edema (NCT04537884)

The phase II trial of the senescent cell lysis drug UBX0101 in the treatment of osteoarthritis (NCT03513016) was recently terminated due to the lack of positive results compared with placebo in the interim analysis

Outlook

Over the past decade, the amount of research in the field of senescent cells has grown exponentially

However, due to the strong heterogeneity of senescent cells in both form and function, and the phenotype of senescent cells can also vary according to cell types, source tissues, remaining tissues, functional effects, and their senescence induction methods.

Meet the challenge and keep exploring
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With the continuous extension of human lifespan and the accelerated global aging process, can cutting-edge innovative anti-aging treatments make many of today's common "age-related diseases" disappear?