Geroprotection & Aging

Healthy Ageing through Geroprotectors

Population ageing is accelerating at an unprecedented pace - the proportion of people aged 60 and older is projected to nearly double by 2050, reaching approximately 2.1 billion individuals worldwide. While life expectancy continues to rise, these additional years are frequently accompanied by multimorbidity, geriatric syndromes, and prolonged dependency, revealing a widening gap between lifespan and healthspan. Addressing this challenge requires a fundamental shift from treating individual diseases to targeting the core mechanisms of ageing itself - a goal for which computational platforms like Way2Drug are uniquely well positioned.

According to Alexey Moskalev and co-authors, “The founder of scientific "gerontology" is famous Russian and French biologist and Nobel laureate Ilya Mechnikov, who first used the term "geroprotector". The literal translation of "geroprotector" is "protecting against aging". From the initial determination, the primary criterion of geroprotector is the ability to increase the lifespan of model organisms.” A substance may be classified as a geroprotector if it satisfies one or more of the following criteria: it extends lifespan; it slows or reverses processes associated with age-related diseases; it positively influences biomarkers of human ageing; it lacks significant adverse effects; and it enhances overall quality of life. Because ageing is driven by more than a dozen mechanistically interconnected biological hallmarks including: oxidative stress, genomic instability, chronic inflammation, impaired proteostasis, mitochondrial dysfunction, and microbiome disturbances - effective geroprotectors are expected to act on multiple targets simultaneously, making in silico multi-target evaluation not just useful but essential.

PASS GERO: Dedicated Geroprotection Prediction

By employing consistent structural descriptors and a unified mathematical framework, the PASS Online (Prediction of Activity Spectra for Substances) software is capable of predicting over 4 000 biological activities with an average accuracy of approximately 0.95. Based on this methodology, we developed a novel web service, PASS GERO. This service enables the prediction of over 117 biological activities specifically associated with geroprotective effects, achieving an average accuracy of approximately 0.97. The predicted activity profile comprehensively covers all major hallmarks of ageing: inhibition of oxidative stress, preservation of mitochondrial function, maintenance of proteostasis, senolytic and senostatic effects, suppression of genomic instability, modulation of epigenetic regulation, and more.

Validated on Real Compounds

The predictive power of PASS GERO has been directly validated against experimentally characterised compounds. For the grape-seed polyphenol procyanidin C1 - a novel candidate geroprotector - the tool correctly predicted its free radical scavenging, antioxidant, senolytic, and NF-κB inhibitory activities, all of which were subsequently confirmed experimentally. Beyond these verified mechanisms, PASS GERO additionally predicted autophagy induction and antimutagenic effects (Pa > 0.5) that have not yet been tested experimentally, providing concrete, prioritised directions for future laboratory investigation. Importantly, all computational predictions must be substantiated through rigorous validation in appropriate experimental and biological systems.

Personalized Polypharmacological Approach

Because ageing is a highly heterogeneous process shaped by individual genetic, environmental, and lifestyle factors, no single universal "magic pill" is likely to exist. Way2Drug supports a personalised strategy: identifying the most suitable anti-ageing compounds, alone or in combination, that target the specific biological and pathological features of an individual. PASS GERO enables the generation of detailed mechanistic polypharmacology profiles for known drugs such as rapamycin, metformin, and resveratrol, facilitating rational combination design and analog optimisation through iterative structure–activity relationship (SAR) exploration.

How can our research be useful to you?

PASS GERO is a ready-to-use web resource for the following tasks^*:

^* Using local PASS version with the PASS GERO knowledgebase, one may perform the virtual screening in big compounds libraries, to identify candidates with promising geroprotective profiles suitable for subsequent experimental testing.