New Antiaging Senotherapeutics: Senolytics and Senomorphics

Dermatology has previously focused on the prevention of aging primarily through sun avoidance and the use of topical sunscreens. Although UV exposure accounts for the majority of extrinsic aging in most individuals, it does not affect intrinsic aging.

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Is it possible to address the other half of the aging mechanism? The answer may soon be yes, given the focus of many companies on senotherapeutics. Senotherapeutics are small molecule drugs that induce cell death in senescent cells (ie, senolytics class of drugs) or inhibit the pro-inflammatory senescence-associated secretory phenotype (SASP; ie, senomorphics class of drugs) that induces senescence in surrounding cells. Aging impairs the removal of senescent cells, and senotherapeutics can enhance immune clearance.

What are senolytics?

The word senolytic comes from the 2 root words senescence and lytic, meaning to destroy; thus, senolytics are small molecules that selectively induce cell death. The goal of senolytics is to prevent, delay, and reverse the signs of aging by enhancing immunity and removing senescent cells. The drugs that are being investigated for their senolytic effects are repurposed cancer chemotherapeutic drugs administered via pulsed dosing and in lower doses (eg, dasatinib [Sprycel; Bristol Myers Squibb] or navitoclax [AbbVie]). Senolytics selectively eliminate senescent cells by targeting critical enzymes involved in their antiapoptotic (ie, cell survival) mechanisms, such as p53, p21, and numerous others. One of the largest areas of senolytic research relevant to dermatology is wound healing, as reducing the burden of senescent cells may facilitate healing.

What are senomorphics?

Senomorphics modulate the properties of senescent cells without destroying them like senolytics do. Senomorphics suppress the SASP and include drugs such as rapamycin (sirolimus [Rapamune]; Wyeth Pharmaceuticals LLC), everolimus, and apigenin. Thus, senomorphics target nuclear factor–κB, mTOR, and IL-1α. The best studied of these substances is rapamycin, which is an mTOR inhibitor that has been shown to extend lifespan and decrease UV-A–induced photoaging in mouse models.

A familiar senomorphic is metformin, an oral agent for the treatment of type 2 diabetes mellitus. Chronic low-dose metformin administered to human fibroblast cultures reduced the expression of senescence-associated β-galactosidase (SA-β-gal). SA-β-gal is a hydrolase enzyme that catalyzes the hydrolysis of β-galactosides into monosaccharides. It is one of the most commonly used markers for senescent cells because it is easy to detect both in vivo and in vitro. Having a reliable marker for senescence is important, as many different small molecules can be tested for their ability to function as senomorphics.

In the botanical realm, the natural products apigenin and kaempferol are being studied for their senomorphic properties and are already incorporated into senomorphic dietary supplements. Apigenin is a flavonoid found in many fruits and vegetables, such as parsley and celery, and in chamomile tea. Sixty-eight percent of the flavonoids found in the chamomile flowers used to make chamomile tea are apigenin, which can increase the activity of superoxide dismutase and reduce oxidative stress. Kaempferol is a natural flavonoid also found in a variety of foods, including broccoli, spinach, kale, and beans, and in tea. Eating fruits and vegetables may be an excellent way to obtain senomorphics.

Zoe Diana Draelos, MD, is a consulting professor of dermatology at Duke University School of Medicine in Durham, North Carolina, and Dermatology Times’ editor in chief emeritus.