Senolytic drugs: A way to get rid of senescent cells

Priyanka Saha, Amity University Kolkata

Introduction

Senolytics are a special class of drugs that eliminate old or senescent cells (SC) in the body. They are developed to prevent or delay age-related diseases in humans. The word senolytics is connected to “Senostatic” which refers to suppressing senescence. Most of the senolytic agents are in the early clinical human trials for a better understanding of their effectiveness in achieving good health.

Senolytics have been potentially identified as a new way for curing age-related malfunction and disorders in preclinical research. They are known to reduce the number of senescent cells, inflammation, and infirmity in old people. The major senolytic compounds are the reutilized anti-cancerous molecules, like Navitoclax, Quercetin, Fisetin, and Dasatinib.

Most of the senolytic drugs have been observed to prevent or delay cancers, cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, hematological, skin disorders, and complications related to organ transplantation and radiation from cancer treatment. These drugs are also in primary clinical trials for the treatment of diabetes, Alzheimer’s disease, COVID-19, osteoarthritis, osteoporosis, pulmonary fibrosis, eye problems, and bone marrow transplant.

The Discovery of Senolytics

Senescent cells depict resistance towards apoptosis. This apoptosis resistance takes place despite the production of pro-apoptotic SASP (Senescence Associated Secretory Phenotype) factors by the senescent cells.

The hypotheses that were taken into account during the discovery of senolytic drugs are:

1) Senescent cells resist apoptosis which increases pro-survival-anti -apoptotic defenses, and

2) sometimes senescent cells act like cancer cells that do not multiply, are resistant to apoptosis, and show characteristic metabolic changes.

Senescent cells follow SCAP (Senescent cell Anti-Apoptotic Pathway) network which prevents their removal, and this network is extensively found in senescent cells as compared to non-senescent cells. Depending on the type of the senescent cell type, small interfering RNAs (siRNA’s) were effective in decreasing senescent cells viability against anti-apoptotic regulators.

Bioinformatics tools were used to identify compounds targeting the SCAP network that protects senescent cells from apoptosis. 46 such compounds were identified and most of them are already in use as anti-cancerous agents. This comprises Dasatinib (D, a tyrosine kinase inhibitor), Quercetin (Q, flavonoid, makes apple peel taste bitter), and Fisetin (F, flavonoid). The tyrosine kinase inhibitor Dasatinib promotes apoptosis created by dependence receptors (ephrins) by inhibiting Src Kinase whereas the flavonoids act in part by inhibiting BCL-2 members like BCL-xL, HIF-1a, and many other SCAP components. Dasatinib and Quercetin, when used together have the potential to induce apoptosis in both senescent human primary adipocyte progenitor cells and senescent HUVEC’s.

The first senolytic drugs (D, Q, F) were discovered by bioinformatics to find agents that disable the SCAP network. The second generation of senolytic agents (vaccines, immunomodulators) is being identified using traditional drug discovery methods and other drug discovery methods.

The Need for Senolytic Drugs

Senescent cells are quite harmful at old age. These cells are not able to divide or multiply like other cells but can manage to remain alive. Senescent cells affect tumor suppression, wound healing, embryonic/placental growth, and plays a pathological role in age-released diseases as well. As we grow old, these cells get stored at sites of multiple chronic disorders which results in morbidity, mortality, and deterioration of human health. The deleterious senescent cells are resistant to apoptosis by having up-regulation of the anti-apoptotic pathway which defends them against their SASP. This up-regulation allows them to survive for a long time and to kill the healthy cells around them. Senolytics temporarily impair these SCAPs, resulting in apoptosis of those cells with a tissue destructive SASP. As these cells take weeks to re-accumulate or store, senolytics can be administered discontinuously – a ‘hit-and-run’ approach.

Some Potential Senolytic Candidates

1) Senolytic FOXO4-related peptides: When a protein named p53 is reserved in the nucleus by FOXO4, it results in cellular senescence. Later, the p53-FOXO4 interaction is broken down by a peptide which releases p53 in the cytosol and triggers cell death.

2) Navitoclax: Also known as ABT-263, is a chemotherapeutic drug that has the potential to eliminate senescent hematopoietic stem cells (HSCs), muscle stem cells and mesenchymal stromal cells (MSCs).

3) Fisetin: It is a plant-based flavanol belonging to the flavonoid group. It reduces senescence in specific cells in rodents and human adipose tissue cells which indicates that it is highly cell-specific.

4) Dasatinib and Quercetin (D+Q) combination: It is the first identified senolytic drug that showed an impact on the SCAPs and eliminates different kinds of senescent cells in the human body.

5) Piperlongumine (PL): It is a compound derived from Piper species that has numerous effects on tumors, diabetes, pain, neurodegenerative and psychiatric disorders. It decreases cognitive impairment and improves hippocampal function in aged rodents. Although its clinical trial for human usage is still ongoing.

The Potential of Senolytics to Modify Geriatric Medicine

Effective senolytics and its associated agents that delay aging have the potential to transform geriatric medicine. These drugs may have the ability to increase healthspan and delay or alleviate chronic disorders which otherwise cause morbidity, immobility, and decreasing health in people across the globe. Senolytics are believed to delay or treat geriatric problems, along with sarcopenia, immobility, and cognitive disorders.

The use of senolytics in geriatric medicine could modify the treatment and health services in old age people by increasing their lifespan and curing the diseases faced by them. The basics of these drugs have been reviewed and they have moved-up in the clinical trials in the last few years. For its successful usage, clinical geriatricians and scientists dealing biology of aging are needed to study and reveal insights into this topic, to unravel the entire pathway of the senolytics targeting the aging process and senescent cells, while abiding by of social and bioethical norms.

Clinical Strategies To Be Adopted

Modern clinical trial strategies are necessary to understand senolytic drugs’ function in removing senescent cells and delaying the aging process. Parameters such as lifespan cannot be tested in humans. According to the geoscience hypotheses, if a candidate drug targets the fundamental aging process, then it also potentially affects a wide range of pre-existing chronic conditions and age-related problems. The potential clinical trial includes:

A) Concurrent relief of multiple disorders/diseases: Humans, especially the old ones suffer from multiple diseases. The use of senolytics can alleviate disease-related problems like glucose intolerance, cognitive impairment, joint Pai caused by osteoarthritis, hypertension, or low carotid flow. These drugs can also delay the onset of a second age-related disorder for those who are already suffering from one disorder.

B) Treatment of conditions with localized senescent cell accumulation: Disorders like osteoarthritis, idiopathic pulmonary fibrosis, and retinopathies are related to the accumulation of senescent cells. This opens the way for the usage of senolytic drugs in humans.

C) Treatment of accelerated aging-like problems: Senolytics targeting the basic aging process may be useful in treating conditions related to accelerated aging-like phenotypes, including chemotherapy to bone marrow transplantation or childhood cancers, human immunodeficiency infection, or obesity.

D) Reliving fragility: Senolytics may be tested in short-term clinical trials in older adults with frailty which will determine strength, gait, body weight, and other parameters to upgrade.

E) Alleviating potentially fatal disease: Diseases like idiopathic pulmonary fibrosis and primary sclerosis cholangitis, that have no effective treatment are believed to be caused due to accumulation of senescent cells. Senolytic drugs are expected to be a cure for this disease by targeting the senescent cells.

Summary

The main motive behind using senolytic drugs is to eliminate senescent cells that cause an array of health-related issues with age. These agents could interfere and delay, prevent, or alleviate multiple age-related conditions and chronic diseases, leading to increase in lifespan and health quality. For human use, senolytic drugs are still under clinical trial for administrating their effectiveness and toxicity level, for their usage to prevent or delay senescence. Unless such clinical trials are well-established, senolytics should not be used or recommended by physicians for any treatment among general populations. Till then senolytics should be only used and administered carefully for research and developmental purposes under proper supervision of experts, in appropriate laboratorical conditions.

Also read: Dogs distinguish intentional from unintentional behaviour

References:

1. Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: From discovery to translation. Journal of internal medicine, 288(5), 518-536.https://doi.org/10.1111/joim.13141
2. Zhu, M., Meng, P., Ling, X., & Zhou, L. (2020). Advancements in therapeutic drugs targeting of senescence. Therapeutic Advances in Chronic Disease, 11, 2040622320964125. https://doi.org/10.1177%2F2040622320964125
3. Scharping, N. (2020). Senolytics: A New Weapon in the War on Aging. Discover Magazine. https://www.discovermagazine.com/health/senolytics-a-new-weapon-in-the-war-on-aging

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