Chronic repeated low dose THC treatment enhances health-span and the anti-ageing effect of a senolytic treatment

• Applicant: Privatdozent Dr. Andras Bilkei-Gorzo
• Subject Area: Biogerontology and Geriatric Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 541388852

The present research proposal aims to clarify whether chronic low dose THC treatment in aged mice slows down cognitive and bodily ageing. We also ask, whether the combination of THC and senolytic treatment shows a cumulative effect on health-span. The first main aim of our proposed studies is to clarify whether a long-lasting restoration in cannabinoid signalling through repeated chronic low dose THC-treatment slows down brain ageing and increase health-span. We have previously shown that a 28-days long THC treatment improved learning ability and memory in aged animals by restoring synapse densities, expression pattern and epigenetic marks to the level typical to young animals. It is not known, however, whether it is possible to improve cognitive health span in the whole second and third trimester of a mouse life by slowing down brain ageing with repeated THC-treatments. THC exerts its positive anti-ageing effects specifically on neurons and does not significantly influence the ageing phenotype of glia cells. We therefore also hypothesize that a combination of the neuron-specific THC-treatment and the glia-specific senolytic treatment is more effective than the individual treatments. As a second main aim, we will compare the efficacy of the repeated THC and senolytic treatments alone and in combination. Several experimental and clinical evidences prove that brain and bodily ageing interact, therefore we hypothesize that slowing down brain ageing positively affects bodily ageing. We will assess the efficacy of our treatment strategies in reducing age-related functional, molecular, and structural changes in the 15-month-old cohort. We will also examine the long-term impacts of repeated treatments using the 30-month-old cohort on the development of frailty and survival. In Aim 3, to dissect the causal relationship between our treatment strategies, we propose that hypothalamic CB1 receptor activity and its effect on microglial activity plays a key role in the efficacy of THC and senolytic treatment and in their interaction. We will compare the anti-ageing effects of senolytic and THC treatments as well as their combination between control animals and mice with increased hypothalamic pro-inflammatory glial activity due to hypothalamus-specific deletion of CB1 receptors focusing on the reversal of age-related changes after one treatment regime in 15-month-old mice. Lastly, we will create an organ bank to compare also the dynamics of age-related histological changes in peripheral organs in follow up studies, because this important point is over the 3-years time-frame of this proposal.

• DFG Programme: Research Grants