Senolytic vaccine (anti-GPNMB)

A Japanese group at Juntendo and Niigata published this in Nature Aging in 2021 and the headline wrote itself: a vaccine against ageing. What they did is narrower and more interesting than the headline.

The logic starts from a complaint about existing senolytics. Most of them work by blocking anti-apoptotic pathways, which are not unique to senescent cells, so off-target damage in healthy tissue is a live concern. The alternative is to find something on the surface of a senescent cell that is not on the surface of a healthy one, then let the immune system do the killing. They screened transcriptome data from senescent human vascular endothelial cells and picked GPNMB, a transmembrane protein enriched in senescent cells. GPNMB was also raised in the endothelial cells and leukocytes of people and mice with atherosclerosis.

They then did three things in mice. Genetically ablating GPNMB-positive cells reduced senescence in fat tissue and improved systemic metabolic abnormalities in mice on a high-fat diet, and reduced atherosclerotic burden in ApoE knockout mice on a high-fat diet. They immunised mice against Gpnmb and GPNMB-positive cells fell. And senolytic vaccination improved normal and pathological age-related phenotypes and extended the male lifespan of progeroid mice.

Read that last clause carefully, because it is routinely mis-stated. The lifespan result is in male progeroid mice, animals genetically engineered to age abnormally fast, not in normal mice of both sexes. The follow-up work from the same group complicates the story further: GPNMB turns out to be a survival factor that protects lysosomal integrity in senescent cells, and depleting it in mice impaired vascular function and worsened atherogenesis. The same protein you would vaccinate against is doing something protective in the cells that carry it.

No human trial exists. A registry search returns no clinical study of a GPNMB senolytic vaccine.

There is no human evidence. No trial of a GPNMB senolytic vaccine is registered, and nothing has been given to a person.

The honest version of this page is that the vaccine idea is good and the target is unresolved. GPNMB is enriched on senescent cells, which is what makes it usable, and it is also a survival factor those cells depend on, which the same laboratory demonstrated a year later by knocking it down and making mouse vascular disease worse. GPNMB is additionally expressed in healthy tissue including melanocytes, osteoclasts and some macrophages, and it is under investigation as a tumour antigen in oncology, which is another way of saying it is not exclusive to senescent cells. An immune response you cannot switch off, aimed at an antigen that healthy tissue also carries, is a different safety proposition from a drug with a three-hour half-life.

The lifespan claim should be quoted precisely. It is male progeroid mice, a strain engineered to age abnormally fast. It is not normal-lifespan mice, it is not females, and it is not people.

No senolytic of any kind has yet improved a clinical outcome in a randomised human trial. That sentence is the single most useful thing to carry into any senolytic discussion. Senescent cell burden has been reduced in people, by dasatinib plus quercetin, and the field has measured that reduction in skin and fat biopsies. What has not followed is a randomised trial in which people who got a senolytic ended up walking further, breaking fewer bones, or living longer than people who did not. The two randomised trials that tried, in pulmonary fibrosis and in postmenopausal bone turnover, did not separate from control.