DEVELOPMENT OF NATURAL PRODUCT FOR PREVENTING AGING-RELATED DISORDERS

The aging process is a progressive and irreversible loss of physiological integrity that causes a deterioration of body functions and is considered as a preeminent risk factor for leading age-related diseases and increasing the mortality in the world. In light of these considerations, there is an increasing effort to discover and modulate the driving causes of ageing in order to alleviate the healt and economic burden that it produces. Cellular senescence is one of these hallmarks of aging, and has received incremental interest as a key contributor to chronic pathologies and functional decline in late stage of the life by accumulating over time and promoting inflammation. Senescence is a phenomenon in which cells enter into an irreversible cell cycle arrest and this can be triggered by various stimuli such as telomere shortening, DNA damage, radiation, or chemotherapeutic agents. Recent studies have demonstrated that the removal of senescent cells by using senolytic therapy, compounds that selectively eliminate senescent cells, can delay various age-related disorders and rejuvenate damaged tissues. Nonetheless, these agents exhibit limitations concerning selectivity, range of activity, and undesired toxicity. To overcome these restrictions, the project aims to identify novel senolytics with enhanced efficacy by screening a library containing over 2600 natural compounds. Using an automated high-content imaging system with engineered human fibroblasts (IMR-90), a compound named NP-12 was selected during this screening process, exhibiting superior senolytic efficacy without adversely affecting proliferative cells. Subsequently, we investigated different pathways to elucidate the mechanism of senescent cell death induced by the selected candidate. It was observed that NP-12 leads to the upregulation of Cyclophilin D (CypD) and increases sensitivity to opening of the mitochondrial permeability transition pore (mPTP) in senescent cells, making them more susceptible to such stress induction than non-senescent cells. This is due to the activation of a protective mechanism against apoptosis due to better mitochondrial health, while senescent cells with dysfunctional mitochondria are more vulnerable to cell death under similar stress. NP12 is isolated from a fruit extract and the entire extract is currently being tested in aged mice to investigate its potential senolytic effects, given its richness in NP-12. The next step of this project is to examine the pure NP-12 molecule on in vivo aging mouse models, but this requires a large amount of the compound, leading to the experiment being postponed as a future goal. However, the NP12's isolation source, a plant extract, was further tested in aging models which showed promising results for healthier aging.