What Are Senolytics and How Can They Stifle Aging?

Highlights

• According to one theory, senescent cell accumulation reaches a threshold during aging where the immune system cannot control their buildup.
• Animal models have shown that senescent cell buildup facilitates age-related diseases and that senolytics like dasatinib and quercetin alleviate them.
• Completed human trials with senolytics have shown that these compounds improve physical function in frail individuals with a lung condition along with longevity-associated enzyme levels in the urine.

Nearly all cells in the body can enter a state called senescence, where they stop proliferating and can release inflammatory molecules to surrounding cells. These molecules can promote senescence transformation, thereby promoting additional senescence accumulation. Cells enter senescence in response to a multitude of stimuli, like damage, infections, or after going through too many divisions. Cells that are senescent accumulate in organs and tissues as we get older, and they represent a defining characteristic of aging referred to as a hallmark of aging. Aside from serving as an aging hallmark, these cells may also play a causal role in processes of aging as well as age-related diseases.

Senescent cells can have harmful effects on the function of tissues and organs like the kidneys. These harmful effects arise from certain inflammatory molecules within a mixture of senescent cell-secreted factors called the senescence-associated secretory phenotype (SASP). Along those lines, the targeted elimination of senescent cells with compounds called senolytics has been shown to delay, prevent, or alleviate multiple age-related disorders in animal models.

Crossing a Threshold of Senescent Cell Abundance Perpetuates the Spread of Senescence

About 30% to 70% of senescent cells release SASP factors that spread to surrounding cells to initiate their senescence. Under youthful physiological conditions, immune cells in the body are more effective at clearing senescent cells, and many are eliminated within days or weeks after they develop. However, some persist, and one theory states that if a threshold burden of senescent cells is met, these harmful cells accumulate at an increasing rate, likely due to their capabilities of initiating senescence in other cells to propagate the spread of senescence. Under such circumstances, the immune system cannot keep up with clearing newly formed senescent cells, and senescence perpetuates and spreads throughout tissues in a snowball effect.

After passing the threshold of having too many senescent cells during aging, these cells can drive age-related tissue deterioration and disease as well as immune dysregulation. The SASP factors that senescent cells release can also induce a chronic, low-grade inflammatory state in the body associated with aging called “inflammaging.” Consistent with their inflammation-inducing properties, senescent cells have been shown to cause disorders related to tissue inflammation, tissue scarring (fibrosis), and insulin resistance preceding diabetes in animal models.

Senolytics Selectively Eliminate Senescent Cells to Improve Tissue Function and Alleviate Diseases

To counteract the age-related accumulation of senescent cells and the inflammation and diseases they may cause, researchers have identified senolytic compounds. Senolytic compounds eliminate senescent cells by inducing their death (apoptosis). Such senolytics include dasatinib, a drug also used for chemotherapy, along with quercetin and fisetin, which are found in certain fruits like strawberries and apples.

Because different types of senescent cells may use more than one pathway to evade apoptosis and since senolytics only target one or a few of these pathways to induce apoptosis, combining senolytics serves as a way to increase the probability of senescent cell elimination. Along those lines, researchers have performed numerous studies combining dasatinib and quercetin. These studies have shown that dasatinib and quercetin combined alleviate age-related diseases like type II diabetes, heart disease, frailty, kidney and lung fibrosis, and extend maximal lifespan in mice. However, the pathways used to induce apoptosis also exist in non-senescent cells, and off-target effects are a worry for researchers.

Human Trials Show Senolytics Alleviate Age-Related Frailty and Increase Urinary Pro-Longevity Enzymes

Since preclinical studies using mice look promising, the next step for researchers has been to find whether senolytics alleviate age-related diseases in humans. As such, there are a few human trials recruiting participants to find whether dasatinib and quercetin combined improve the number of disease-free years lived (healthspan). One of these is looking at stem cell recipients who typically display signs of premature aging to find whether dasatinib and quercetin mitigate their premature aging.

Other results already published have shown that dasatinib and quercetin improve physical function in frail patients with a lung scarring condition (idiopathic pulmonary fibrosis). Moreover, another study of patients with idiopathic pulmonary fibrosis showed that dasatinib and quercetin combined increase urinary levels of an enzyme linked to longevity called ⍺-klotho. These results give promise that using senolytics can in fact extend the number of healthy, disease-free years we live.

Anti-Aging Researchers Continue Their Search for More Effective Senolytic Compounds

From preclinical trials using mice to completed human trials, senolytics show promise for selectively eliminating senescent cells to improve tissue function and extend people’s healthspan. Not only that but researchers are continuing their search for new, more effective senolytics that may spawn even better compounds with which to target senescent cells. Since human trial results have already shown the promise of senolytics at improving physical function in a population with frailty, it may only be a matter of time before aged individuals can take them to extend their years lived in good health.