Karma, Karma, Karma Cholesterol: 25-Hydrocholesterol is a Promising Senolytic to Support Healthy Aging

We make seemingly innumerable cells to maintain our bodies over a lifetime. But at some point, some of our cells will get stuck in a state of arrest in cell growth and replication called senescence. This cellular phenomenon has been shown to directly influence aging and longevity, shortening health and lifespan.  

And as the link between senescence and mortality has come into clear sight, there’s been a mad dash towards the discovery of senolytics — compounds that can mitigate or remove senescent cells by targeting genes that promote the survival of senescent cells. A study from the Buck Institute for Research on Aging identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent and novel senolytic.

“Given that 25HC shares no common molecular motifs with other senolytics, it appears that this molecule represents a brand new class of potential interventions,” said Buck professor Simon Melov, senior scientist on the study. “It’s most likely going to be useful in multiple contexts of senescence...We’re continuing to refine this molecule and its target in order to understand how it works in the mouse and human cell types.”

The light and dark of senescence

Since senescent cells increase with aging, many researchers assume that senescence contributes to aging. However, this view undervalues what conceivably is the primary purpose of senescence, which is to prevent the propagation of damaged cells and to trigger their demise by the immune system. Therefore, senescence may be a beneficial compensatory response that rids tissues of damaged and potentially harmful cells.

However, this cellular checkpoint requires an efficient cell replacement system that involves clearance of senescent cells and mobilization of progenitors — descendants of stem cells that create a diversity of cell types — to re-establish cell numbers. In aged organisms, this turnover system may become inefficient or exhaust the regenerative capacity of progenitor cells, eventually resulting in the accumulation of senescent cells that may aggravate the damage and contribute to aging.

25-hydroxycholesterol is a senolytic in multiple cell types

In this journal pre-proof published in iScience, the research team sought to identify robust senescence-induced genes as potential targets for senescent cell elimination. They found that the gene Crystallin Alpha B (CRYAB), which prevents the aggregation of misfolded proteins to inhibit cell death, is a gene strongly induced by senescence. The Buck Institute researchers found that CRYAB is upregulated upon senescence in nine different cell types and two species, suggesting it can be a common senolytic target for diseases of multiple organs.

The research team, led by Chandani Limbad and Ryosuke Doi, then screened for senolytic compounds that targeted CRYAB. They identified 25HC, which blocks CRYAB aggregation, as a senolytic in mouse and human cells in culture and in the skeletal muscle of mice. 25HC is an oxysterol, an oxygenated derivative of cholesterol. Other oxysterols, including 24HC and 27HC, may also exert senolytic effects, and the Buck Institute researchers speculate that oxysterols may be a promising new class of senolytics with the potential to support healthy aging.

They showed broad utility for the senolytic potential of 25HC in various cell types, with the most robust outcomes in cells derived from skeletal muscle. 25HC showed stronger effects in skeletal muscle tissue than other tissues and substantially inhibited the levels of several secreted factors that cause senescence in skeletal muscle. Aging is linked with chronically increased inflammatory signaling molecules, known inducers of muscle atrophy. This observation suggests that 25HC may improve age-related muscle atrophy via senolytic effects in future studies.

“This is a significant breakthrough for evaluating the efficacy of candidate senolytics drugs,” he said. “Otherwise, how do you know whether the intervention is having any effect unless you’ve got some massive effect on functional outcomes? In aging research, we don’t often have massive improvements when it comes to function, but even small effects can be beneficial.”

What’s next for 25-hydrocholesterol?

Considering 25HC has multiple roles in immune response, including beneficial and harmful effects, it will be important to further test 25HC in mice for safety and efficacy as a senolytic in living animals and humans. Each senolytic may have different efficacies based on tissue specificity, potency, and safety. The apparent tissue specificity of 25HC may relate to differential tissue accessibility within the animal or additional dosing optimization. Functional consequences of 25HC treatment in aged animals are a clear area for additional investigation in future studies.

This study has several limitations. Primarily, the study only verified the senolytic potential of 25HC indirectly using 15-dPGJ2, a recently identified marker that allows the detection of destroyed senescent cells. The Buck Institute researchers also measured a small but significant increase in muscle wet weight of aged animals after treatment with 25HC. While the researchers did not delve into whether 25HC leads to functional improvement, it will be interesting to determine if 25HC treatment improves other tissues or organ function in aged animals by reducing senescent cell burden.

References:

Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z.S., Daya, R., Seals, D.R., Campisi, J., Melov, S., Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types, ISCIENCE (2022), doi: https://doi.org/10.1016/j.isci.2022.103848.