When tech billionaires and other financial ‘masters of the universe’ types think about their own mortality, a significant number decide it simply isn’t for them. The result: huge investments in research to find the biochemical keys to unlock the mysteries of aging so they can be slowed or reversed. While a beneficial link between physical activity and mental acuity has been posited for centuries, laboratory demonstrations that exercise has specific regenerative effects on the brain only began to appear in 1999. Interestingly, those early investigators found that running - but not swimming - produced a significant increase in cell proliferation and neurogenesis in dentate gyrus of adult mice. Once it was established that physical exercise is a strong positive modulator of adult hippocampal neurogenesis, the search for molecules that mediate this process, especially cytokines or other secreted hormone-like proteins, accelerated rapidly. In 2019, the chemokine XCL1 was identified as a promoter of neurogenesis that is upregulated in the plasma of exercised mice. Dr. Tara Walker of the Queensland Brain Institute at the University of Queensland and her colleagues confirmed the essential role of XCL1 using cell based assays and an XCL1 knockout mouse and published their findings in Scientific Reports.

Another study by the same group published in August 2023 identified CXCL4 (also known as platelet factor 4, or PF4) as a pro-neurogenic platelet-derived exerkine and observed molecular changes elicited by exercise in platelets from young and aged mice. They showed that exercise increased circulating levels of CXCL4, and platelets are necessary to translate the rejuvenating effects of exercise to the aged brain. Treatment with recombinant chemokine increased adult hippocampal neurogenesis in aged mice (see figure) and prevented age-related loss of memory and learning in a mouse model of aging. Two other groups reported similar findings in papers published at the same time in Nature and Nature Aging.

20-month-old C57BL/6J mice receiving intravenous (i.v.) PF4 injections showed significant increases in Ki67+ cells in the subgranular zone, and PF4 increased the percentage of proliferating DCX+ cells and the total number of DCX+ cells in the dentate gyrus compared to saline-treated controls [excerpted from Figure 5 of Leiter et al, Nat Comm 14 4375 (2023)].

According to Dr. Tara Walker of the Queensland Brain Institute at the University of Queensland and senior author of the article in Nature Communications, “PF4 is the most powerful protein we have yet identified for promoting neurogenesis and preserving learning and memory in aging mice”. Among the questions to be answered is how CXCL4 exerts its anti-aging effects. CXCL4 is an orphan chemokine, with no known receptor. It will be important to understand the mechanism of action to take full advantage of CXCL4’s beneficial properties in the quest for lifespan and healthspan extension.

As noted in a previous post, CXCL4 is the subject of intense interest as the auto-antigen responsible for development of heparin-induced thrombocytopenia (HIT) as well as the rare COVID complication, vaccine-induced Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT). Recombinant CXCL4 protein supplied by Protein Foundry is a key component of a new clinical diagnostic test for HIT. Protein Foundry is the best source for native or C-terminally tagged recombinant human and mouse CXCL4 proteins. Inquire about custom CXCL4 variants that can be produced on demand.