Quest for Immortality: Progress in Senolytics

Senescent cells are often called “zombie cells,” because they don’t want to die. They just hang around in your body and cause cancer, dementia, diabetes, wrinkled skin, arthritis, and a host of other painful and disfiguring signs of aging.

Eliminating zombie cells is one of the 7 main approaches to anti-aging taken by the famous SENS research program. There are now about 100 drugs in development for removing senescent zombie cells. These drugs are called “senolytics.” A Japanese team has claimed to have developed a vaccine to remove zombie cells.

Researchers have been able to reverse many signs of aging in mice using senolytic drugs, although research in humans is scant to this point.

Senolytic therapies to selectively destroy senescent cells in old tissues have produced rapid rejuvenation in mice, turning back many different age-related diseases in many different studies. Senescent cells actively maintain a disrupted, inflammatory state of tissue when not cleared effectively by the immune system. Initial human trials of the dasatinib and quercetin combination (readily available to self-experimenters as well, prescribed off-label) have produced promising results. But as the authors of this paper note, there is still far too little human data to satisfy the cautions of regulators. Many more trials should be underway, particularly for dasatinib and quercetin, to definitively establish that this is a path worth pursuing, and allow the physician community to prescribe senolytics widely in the aged population.

Fight Aging

A recent research study by Mayo Clinic researcher James L. Kirkland helps to explain one possible way that senolytic drugs are able to reverse some signs of aging:

Senolytics developed at Mayo Clinic and given once clear the bloodstream of senescent or “zombie” cells. These cells contribute to multiple diseases and negative aspects of aging. This study shows that the removal of senescent cells significantly boosts the production of a protective protein called α-Klotho.

“We show that there is an avenue for an orally active, small-molecule approach to increase this beneficial protein and also to amplify the action of senolytic drugs,” says James Kirkland, M.D., Ph.D., a Mayo Clinic internist and senior author of the study.

The researchers first showed that senescent cells decrease levels of α-Klotho in three types of human cells: umbilical vein endothelial cells, kidney cells and brain cells. They also demonstrated through using the senolytics desatinib plus quercitin in three types of mice that α-Klotho was increased. They also showed that after administering desatinib plus quercitin in clinical trial participants with idiopathic pulmonary fibrosis, α-Klotho also increased.

MedXpress

Full Text research study discussed above

More on the Klotho protein

More on the drug Dasatinib used in treating leukemias and a key senolytic drug

Dr. Kirkland has a useful lecture on YouTube discussing the concept of senescent cells and senolytic treatments, embedded below.

The featured lecture by James L. Kirkland MD, MPH, begins at about the 8 minute mark:

Below is the abstract from a full text review article on senolytic drugs from the Journal of Internal Medicine:

Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using a hypothesis-driven approach. SC accumulate with ageing and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighbouring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP. Because SC take weeks to reaccumulate, senolytics can be administered intermittently – a ‘hit-and-run’ approach. In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders as well as complications of organ transplantation, radiation and cancer treatment. As anticipated for agents targeting the fundamental ageing mechanisms that are ‘root cause’ contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans. Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer’s disease, COVID-19, osteoarthritis, osteoporosis, eye diseases and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.

Full Text “Senolytic Drugs” from 19 July 2020 JIM

Besides the senolytics, among the more promising near-term anti-aging therapies include the use of Klotho protein (mentioned above), a rapamycin-like drug called Everolimus, a protein labelled GDF11, and a few others that I will discuss in a later article.

I have been recommending the supplements quercetin and resveratrol along with a number of other phytosupplements for over 16 years. If you are going to take anything stronger than moderate doses of plant-based supplements, be sure to consult someone with expertise in their use.

Of course it will take some very strong medications to reverse aging and extend the human lifespan significantly. Every medication has side effects, some of them extremely serious and long-lasting. Nevertheless, many of the medications in the drug pipeline for treating aging are not likely to have side effects any more severe than some of the more common medicines used for hypertension and diabetes. I am encouraged by the results of recent studies.

More:

A longer-term approach to anti-aging that involves reprogramming the genome

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