▎ WuXi AppTec content team editor
Aging refers to the process of gradual decline in the physiological functions of the body as we age. Aging is not only a fundamental driver of chronic disease and functional decline in old age, but can also be accelerated by the coexistence of multiple chronic diseases and geriatric syndromes, resulting in different individuals with different risks of new disease, disability or death.
Senescent cells are an important driver of individual aging. In recent years, with the continuous deepening of anti-aging related research, the search for effective anti-aging drugs and nutrients, and the intervention of senescent cells through them have become a hot research field. Recently, Nature Aging published a blockbuster review, which details the signaling pathways and targets related to senescent cells, and summarizes the latest progress of anti-aging drug-related research in recent years.
Screenshot source: Nature Aging
Biomarkers of senescent cells and therapeutic strategies
The accumulation of senescent cells is thought to be an intrinsic underlying mechanism by which senescence occurs. To date, researchers have found that senescent cells can affect the occurrence of disease and death in multiple systems/organs such as cardiovascular, lung, nerve, kidney, liver, infection, musculoskeletal, and endocrine systems.
The paper points out that cell cycle arrest is a prerequisite for aging, and the aging cell cycle block signal is mainly located in the p53/p21 and RB/p16 pathways. A large number of experiments have confirmed that the accumulation of p21 and p16 is related to cellular senescence and can be used as a biomarker for it. In addition to p53/p21 and RB/p16, including cell morphological characteristics, mitochondria, lysosomals, and nucleus changes, etc., can also be used as a means of identification of senescent cells, these indicators have different sensitivity and specificity.
▲Senescent cell characteristics (Image source: Reference[1])
It is worth noting that in addition to cellular growth arrest, another important feature of cellular senescence is the production of an aging-related secretion phenotype (SASP) that is usually accompanied by it. SASP consists of a series of cytokines, matrix remodeling enzymes, microRNAs, and small molecule metabolites. Along with different stress sources, SASP can produce different mechanisms of cellular senescent effects.
▲Manifestations of senescent cell heterogeneity, such as different aging induction methods, cellular environments, and aging-related secretion phenotypes (Image source: References[1])
Based on the mechanism of action of senescent cells, the current therapeutic strategies for eliminating senescent cells are mainly divided into two categories:
The first category: selective killing of senescent cells, known as "Senolytic therapy";
The second category: eliminating the production and secretion of SASP in senescent cells, is called "Senomorphic therapy".
Since Senomorphic therapy is "symptomatic rather than curative" and usually requires long-term continuous administration, "Senolytic therapy" that directly targets senescent cells is highly anticipated. There is currently a large amount of preclinical evidence that Senolytic therapy can not only intervene in the development of a variety of diseases, but also serve as an important part of regenerative repair therapy.
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.
Recent research progress in anti-aging cell drugs
The first published clinical study of Senolytic therapy
A label-open pre-trial of 14 patients with idiopathic pulmonary fibrosis (NCT02874989) who received a combination of dasatinib and quercetin (D+Q) orally over a 3-week period. Five days after the completion of the last dose, patients improved their 6-minute walking distance, walking speed, seat standing ability, and simple fitness assessment scores. Based on these preliminary data, the researchers are planning a larger, placebo-controlled clinical trial of D+Q for idiopathic pulmonary fibrosis.
Several other clinical trials are also underway 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 pediatric tumor patients (SENSURV, NCT04733534), age-related osteoporosis (NCT04313634), etc.;
Fisetin treats debilitating symptoms in elderly women (AFFIRM, NCT03430037), diabetes mellitus and chronic kidney disease (NCT03325322), pediatric tumor patients (compared to the D+Q protocol in the SENSOV trial), age-related osteoporosis (compared to the D+Q regimen in NCT04313634), osteoarthritis (NCT04210986), etc.;
Bcl-xL inhibitor UBX1325 treats diabetic macular edema (NCT04537884). It is worth mentioning that UBX1325 is the first senolytic therapy drug to be evaluated in an ophthalmic clinical trial. In clinical trials, the vast majority of patients treated with a single injection of UBX1325 showed rapid improvement in several key clinical indicators related to disease progression. At present, the phase 2a clinical trial of UBX1325 has completed the first case of drug administration, and data is expected to be obtained in the first half of 2022, which is worth looking forward to.
prospect
In the past decade, the number of studies in the field of senescent cells has grown exponentially. A range of compounds from different sources based on Senolytic's therapeutic strategies have been found to have potential anti-aging activity, and some of them have entered clinical trials, and together these drugs are driving the continuous development of anti-aging research.
However, due to the strong heterogeneity of senescent cells in form and function, and the senescent cell phenotype can also vary according to the cell type, source tissue, surviving tissue, functional effects and their aging induction methods, etc., research in this field is full of huge challenges, and no anti-aging related drugs have been approved for marketing so far.
Rise to the challenge and keep exploring. As human life expectancy continues to increase and the global aging process accelerates, can cutting-edge innovative anti-aging therapies make many of today's common "age-related diseases" disappear?
On January 11, 2022, WuXi AppTec will join hands with the Singapore Science and Technology Research Agency (A*STAR) and the Davos Alzheimer's Collaborative to jointly hold the "First Healthy Ageing Forum" online, where nearly 30 top aging experts from the United States, the United Kingdom, Singapore and China will gather to point out the future direction of healthy aging. Dr. Sebastien Thuault, Editor-in-Chief of the journal Nature-Aging, will also be one of the forum guests to discuss the current status of anti-aging research.