Focus on frailty over aging

ARDD 2021: Novartis research scientist reveals shift towards targeting frailty, Insilico announces partnership with Gray Matter, aging clocks and much more.

Yesterday at the 8th Aging Research and Drug Discovery Meeting (ARDD) we saw various interesting talks highlighting new ways to target aging and the decline that accompanies it.

Anne Brunet, Stanford University

Anne-Ulrike Trendelenburg from the Novartis Institutes for Biomedical Research gave a brilliant presentation on pathways that should be targeted to treat age-related diseases, and how her research is shifting away from aging and towards defining and targeting frailty.
Novartis’ research has highlighted five recommendations to guide the future of age-related disease targeting. Firstly, focusing on healthspan as opposed to lifespan, which will have the biggest impact on patient lives, adding quality of life to years, over adding years to life.

Better multimorbidity models needed

Trendelenburg also highlighted targeting multimorbidity, rather than continuing to focus on treating each individual disease, which is said to be ineffective and expensive. The team from Novartis want to develop better multimorbidity models in order to progress another of their recommendations, which is to target frailty over age through clinical trials.

Targeting frailty over individual age-related disease, shifting the common pathways focussed on, is an exciting development for longevity. Frailty, the accumulation of deficits leading to loss of independence, has been defined by the Rockwood Clinical Frailty Scale.

Novartis aims to use this to tackle age-related disease from a broader standpoint, and has already shown the huge potential that geroprotectors can have when targeting the mechanisms behind aging, both delaying and preventing the progression of multimorbidity development. Trendelenburg explained that geroprotectors are showing increasing evidence of efficacy in preclinical models, for example with senolytics, rapalogs and metformin.

Gut health, brain health and more

Yu-Xuan Lu, from the Max Planck Institute for Biology of Ageing, also spoke about geroprotectors and shifting the use of them to newer targets. Yu-Xuan explained the potential of rapamycin as a geroprotector that can have epigenetic influence, targeting and promoting gut health and longevity. In his studies, rapamycin increased histone expression in the intestines, which may be linked to an increase in gut health, and leading to the conclusion that the TORC1-histone axis may be a good potential new target for aging.

From gut health to brain longevity, Alice Ruixue Ai from the University of Oslo, introduced the concept of using artificial intelligence for the rapid identification of drugs for treatment of Alzheimer’s Disease. She explained the vital need for therapeutic intervention of AD, and discussed the extreme cortical atrophy seen in the brains of AD patients, which is exacerbated by mitochondrial dysfunction. Ruixue Ai then spoke about the promise of utilising machine learning to enable accurate identification of potent mitophagy inducers, highlighting defective mitophagy as a potential drug target.

Insilico and Gray Matter join forces

On the subject of brain longevity, Insilico Medicine announced a strategic AI-driven research and development collaboration with Gray Matter to fight age-related cognitive decline. The companies will focus on peptide-based interventions against cognitive decline, age-related CNS disease and aging as a whole. Both companies aim to speed up drug discovery of new therapeutic targets for peptide therapy and have come together in a strategic partnership to bring that goal to life.

“We aim to develop a new generation of safe and effective therapies to help patients live longer, healthier lives with their cognition intact,” said Alexey Strygin, co-founder and CEO of Gray Matter. “We see a remarkable synergy between our rapid iterative approach based on proprietary peptide discovery engine Reptide and AI-powered target discovery by Insilico Medicine.”

Cell-type specific aging clocks

As the afternoon talks progressed, we heard from Anne Brunet from Stanford University, discussing the mechanisms of brain aging and rejuvenation. She asked whether single RNA-sequence data could be used to build cell-type specific aging clocks. To date, aging clocks have been built using large bulk data sets, whereas Brunet proposes a clock that allows for single cell resolution.

Brunet described how, using mice models, her team has successfully utilised single RNA-sequence based clocks to accurately predict cell-type specific chronological age across cohorts. They trialled various rejuvenation interventions, including young blood and exercise, to assess their effect on different cell types. When used in combination, the interventions targeted different cell types and so could be used together to combat aging from multiple targets. Brunet’s work highlights the importance of a cell-type specific aging clock for further study into the efficacy of potential new rejuvenation interventions.

Images courtesy of ARDD