Senolytics

What it is

Senolytics are drugs that exploit the survival pathways senescent cells rely on (the senescent-cell anti-apoptotic pathways, SCAPs) to selectively kill them while sparing healthy cells. The best-studied combination is dasatinib + quercetin (D+Q); the flavonoid fisetin is also investigated.

Why they’re of interest

In aged mice, periodic senolytic dosing clears p16⁺ senescent cells from many tissues and improves multiple healthspan endpoints — physical function, frailty, glucose tolerance, lung fibrosis, osteoporosis — even when started late in life. See also Cellular senescence.

Mechanism

Different senescent cell types depend on different SCAPs:

• Dasatinib (a tyrosine kinase inhibitor) targets ephrin- and src-family signalling.
• Quercetin targets BCL-xL and PI3K.
• Fisetin targets PI3K and other survival pathways and has activity against multiple senescent cell types.
• Navitoclax (ABT-263) is a BCL-xL/BCL-2 inhibitor with robust senolytic activity but significant haematological toxicity.

Human evidence

• First-in-human pilot of D+Q in idiopathic pulmonary fibrosis showed improved physical function over 3 weeks.
• Pilot data in diabetic kidney disease showed reduced senescent-cell burden in adipose tissue.
• No large RCTs with hard endpoints yet.

Safety

Dasatinib has a well-known oncology side-effect profile (cytopenias, pleural effusion, QT prolongation, hepatotoxicity) when used continuously. Senolytic protocols use intermittent “hit-and-run” dosing to minimise exposure, but safety data at that schedule are limited. Fisetin appears better tolerated but its bioavailability and efficacy in humans are debated.

Related entries

See also: Cellular senescence, Chronic inflammation.