CASIN Alters Epigenetic State to Produce Lasting Improvement in Aged Stem Cell Function

In recent years, researchers have shown that a single injected dose of CASIN, an inhibitor of CDC42, can improve immune function in old mice, resulting in a lasting gain in health and extended life span. CASIN appears to work by altering epigenetic state in the hematopoietic stem cell populations responsible for producing new immune cells. This is also observed to be the case in other stem cell populations. Raised levels of CDC42 are observed with aging, and have been shown to impair hematopoietic stem cells. This is the case in both mice and humans, so there is some hope that some form of CDC42 inhibition can be used as the basis for a human therapy.

Mogling Bio was recently founded to develop therapies based on the results obtained with CASIN. As I understand it, while CASIN appears safe in animal studies, it isn't as bioavailable as might be desired. The animal doses are large enough that human equivalent doses would require an intravenous infusion rather than a simple injection. The Mogling Bio founders are likely to work on alternative approaches, or tinker with the structure - the usual approach for a new biotech company starting from the position of an interesting compound. That compound is the foundation for improvements that can be patented, providing the monopoly required to support the high company valuation that is needed to raise the sizable funding required to enter the regulatory process. It isn't the best of systems, given the incentives it places on development.

Still! Therapies for which a single dose produces a lasting effect, and where that effect is visible rejuvenation of function in old animals, are much more intriguing than those that require constant dosing over time. I would imagine that we'll see some interest in the self-experimenter community regarding CASIN as matters move ahead with development based on this compound, though (a) the logistics of use, given the large doses and need for injection, make it a more challenging project than is the case for most compounds, and (b) there is no human safety data, perhaps the more important point here. There are other CDC42 inhibitors with at least some human data, predictable emerging from the cancer research community, but these are not specific inhibitors of CDC42, and it is something of a question as to whether they would have similarly useful effects as CASIN.

Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice

The ability to restore or rejuvenate aged tissues by targeting endogenous stem cells is a central goal of regenerative medicine. However, systemic rejuvenation of aged stem cells remains a challenge and it is still unclear to what degree do stem cells contribute to overall organism health- and lifespan. Here, we show that a brief systemic treatment of aged mice with the Cdc42-activity inhibitor CASIN improves the regenerative potential of endogenous aged muscle stem cells (MuSCs) and hematopoietic stem cells (HSCs) in vivo.

We report that after CASIN treatment aged MuSCs divisional kinetic and myogenic capacity in vitro are enhanced and, after injuring the muscle in vivo, tissue regeneration is improved. Supporting that the MuSC improvement after CASIN might contribute to extend mouse healthspan, CASIN mice performed better than aged control mice in endurance and strength tests in steady-state and also after damage. Moreover, we report on systemic CASIN affecting Cdc42 and tubulin polarity as well as H4K16ac epigenetic polarity in aged HSCs. The data on H4K16ac obtained by histological analyses of whole mount bone marrow sections aligns to those previously reported on the DNA-methylation-based epigenetic clock and strongly support at least some traits of epigenetic rejuvenation in HSCs after systemic CASIN treatment.

Furthermore, the histological analysis shows an intriguing effect of CASIN also on aged HSC localization, which after the treatment is closer to arteries and endosteum, like young blood stem cells. At the transcriptional level, stress response, and inflammation constitute the major signaling pathways targeted by CASIN in vivo. Consistently, we have previously reported a significant reduction in the levels of inflammatory cytokines (IL1α, IL1β, and INFγ) in peripheral blood serum of aged mice after in vivo CASIN treatment. These same cytokines were also shown by others to play critical roles in aging of the blood and other tissues

The hematopoietic system is the carrier for many rejuvenation factors, and this leaves open the possibility that rejuvenating aged HSCs might represent an effective strategy to improve aging of the whole organism. Here we show that upon transplantation rejuvenated blood stem cells are sufficient to increase murine lifespan of aged immunocompromised mice. Altogether these results raise critical considerations for refining the targets and goals of anti-aging strategies focusing on a possible central role of HSCs and of the hematopoietic system. To note, previous data associated increased Cdc42 activity to aging in humans and in aged human HSCs, supporting the translational potential of these findings.

These data, together with the recent data supporting an improved activity of aged intestinal and hair follicle stem cells after CASIN treatment support that the increased activity of Cdc42 with aging impairs the function of several somatic stem cells in different tissues. Therefore, systemic treatment with CASIN can elicit distinct positive biological effects in vivo, which might depend on the doses and way of administration. Besides, recently Cdc42 activity has been shown to limit the lifespan of the budding yeast, hinting at a phylogenetically conserved mechanism of the Cdc42-polarity axis in affecting organism aging.