Longevity: Anti-ageing drugs, watch out, here we come…

Advances in multi-omics, artificial intelligence (AI), deep learning (DL), ageing biomarkers, precision imaging, ageing clocks, robotics, and smart technologies have enabled researchers to identify common pathways that can be manipulated with drugs, and promising data is starting to emerge in early human clinical trials.

According to the World Health Organization (WHO), by 2030, one in six people in the world will be aged 60 years or over, and the number of persons aged 80 years or older is expected to triple between 2020 and 2050 to reach 426 million. Although we are living longer, we still spend half of our lives in poor or moderate health.  

Recent advances in longevity medicine

The past 20 years have seen an exponential increase in our understanding of how ageing leads to changes at the molecular and cellular levels. Changes in diet and non-strenuous exercise can influence longevity, for instance. Dietary restriction (DR), has been shown to extend the lifespan of numerous organisms, and supplementing with NAD+ precursors can prevent age-related conditions, including muscle dysfunction, skin ageing, and heart inflammation. Several signalling pathways - AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), Insulin-like growth factor 1 (IGF1)–insulin, mammalian target of rapamycin (mTOR), and serine/threonine kinase 11 (STK11) - collectively alter in old age to activate mitochondrial dysfunction, inflammation, and cellular senescence. 

Interestingly, anti-aging activity has already been demonstrated in a variety of FDA-approved drugs, including anti-cancer agents mTOR inhibitor Rapamycin, and the anti-diabetic agent metformin, an AMPK activator (Table 1). In 2019, the US FDA approved the Targeting Aging with Metformin (TAME) Trial, which will test the effect of metformin on age-related chronic diseases in 3,000 participants at 14 leading US research institutes, over six years. 

Several companies are now looking to repurpose these small-molecule drugs and/or develop new and improved versions to target age-related conditions.  In April 2024, Rubedo Life Sciences completed a $40 million Series A financing round to advance its lead candidate RLS-1496 in chronic atopic dermatitis and to develop its preclinical candidates that selectively target senescent cells in pulmonary diseases. In March 2024, CA-based Aeovian Pharmaceuticals raised $50 million in Series A financing to advance its innovative platform of selective mTORC1 inhibitors, AV078, AV805, and AV505, for anti-ageing diseases. In October 2023, US-based Amplifier Therapeutics secured $33.25 million in private equity to accelerate its R&D programmes. ATX-304, is a small molecule, AMPK, and mitochondrial activator, in Phase 1/2 for cardiometabolic diseases, and the company has partnered with Tornado Therapeutics to develop its next-generation mTOR inhibitors, TOR-101 and TOR-103, in age-related diseases. 

Table 1: FDA-approved drugs with anti-ageing activity. Source: modified from Alex Zhavoronkov, 2024 

X

- Compound inhibits the hallmark of ageing; 

X

- Role in ageing phenotype or lifespan

Alex Zhavoronkov, founder & CEO of Insilico Medicine, stated that he “firmly believes that the repurposing of FDA-approved drugs with demonstrated anti-ageing potential represents a highly promising and cost-effective approach to addressing the growing burden of age-related diseases. This approach aligns with Insilico’s dual-purpose target discovery strategy.”

According to Zhavoronkhov, “AI and specifically DL have become pivotal in identifying novel targets that modulate the hallmarks of ageing. AI excels in analysing vast multi-omics datasets, integrating genomics, transcriptomics, and proteomics to unravel protein interaction networks and the intricate biological processes underlying aging. This capability is crucial for understanding aging-related pathways and hallmarks.” To this end, Insilico Medicine has developed an in-house AI-powered target discovery engine, PandaOmics, incorporating the hallmarks of ageing assessment to identify a list of therapeutic targets specific to age-related diseases. 

The company has identified numerous novel targets for anti-ageing, and age-related diseases. For instance, Insilico’s leading drug candidate INS018_055 targets Traf2- and Nck-interacting kinase (TNIK), which is not only a novel target against IPF identified by PandaOmics, but also has the potential for metabolic diseases, cancer, and anti-ageing.”

Leading academic institutes have also identified several promising age-related targets that may warrant further investigation. In July 2024, researchers at the Duke-NUS Medical School published a study in Nature demonstrating that anti-interleukin-11 (IL-11) protects mice from age-associated pathologies and extends their lifespan. In March 2024, scientists at Stanford University showed that antibody-mediated depletion of aberrant stem cells can help diminish age-associated inflammation and strengthen acquired immune responses. And, in January 2023, Dr David Sinclair and his colleagues published an article in Cell that showed the loss of epigenetic function can accelerate the hallmark of ageing and that “ICE” (inducible changes to the epigenome) can be used to reverse the effects of ageing in mice. 

Investment in longevity research

Over the last decade, longevity investment has gradually evolved attracting $0.5 billion in financings in 2013 and peaking at $6.2 billion in 2021, according to Longevity. Technology. In September 2021, a consortium of biotech, clinical, and academic institutes launched the Swiss Longevity Science Foundation (LSF) to fund up to $1 billion in early-stage ageing research. Since 2021, numerous start-up companies have attracted private investment and these funds have largely been channelled into the development of reprogramming agents.

In 2021, Rejuvenate Bio completed a $10 million Series A financing and used these funds to develop a pipeline of partial reprogramming agents using the Yamanaka factors, specifically OCT4, SOX2, and KLF4 (OSK). Its lead programme, RJB-0402, a liver-directed fibroblast growth factor 21 (FGF-21) gene therapy preserves cardiac structure and function and the company expects to initiate an investigational new drug (IND) for arrhythmogenic cardiomyopathy shortly. The cryptocurrency company Coinbase’s co-founder Brian Armstrong and venture capitalist Blake Byers founded NewLimit, an ageing-focused biotech backed by an initial $110 million investment. The company secured a further $40 million in Series A funding to develop its epigenetic reprogramming therapies.

In 2022, Neurotrack attracted $10 million in Series D funding to develop cognitive health programmes. Co-founders Rick Klausner and Hans Bishop launched Altos Labs, an epigenetic reprogramming company with $3 billion in initial financing from investors including Yuri Milner and Jeff Bezos. Retro Biosciences, secured initial funding of $180 million and Turn Biotechnologies raised $2.5 million to use mRNA medicines to focus on tissue reprogramming. 

In 2023, UK-based Clook.bio raised $4 million to leverage its human induced pluripotent stem cells (hiPSCs) and CRISPR screen to identify biomarkers and gene candidates to target cellular rejuvenation. Verve Therapeutics completed an IPO and raised $143.8 million. It expanded its collaboration with Eli Lilly to develop VERVE-101, VERVE-102, and VERVE-201, in vivo gene editing programmes targeting PCSK9, ANGPTL3, and LPA, genes that increase the risk of atherosclerotic cardiovascular diseases (ASCVD). 

And, in 2024, UK-based Genflow Biosciences raised £715,000 through the placing and subscription for new stock organised by Capital Plus Partners. The company has made significant progress and plans to file an IND for its lead compound, GF-1002, an exo-AAV expressing cDNA of centenarian variant sirtuin 6 (SIRT6), for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). It also has GF-1003, GF-1005, and GF-1004 in preclinical development and has established collaborations with EXO Biologics, UCB, and IvexLabs. 

Future outlook

In October 2023, researchers from the University of Oslo and, the University of Chicago Pritzker School of Medicine published an article in the journal Aging Cell, where they used Insilico Medicine’s PandaOmics (see above) to identify 22 dual-purpose target candidates for anti-ageing and anti-cancer treatment. One candidate, histone demethylase KDM1A, has since been shown to significantly extend lifespan in an ageing research animal model and has anti-cancer activities in clinical studies in colorectal and triple-negative breast cancer.

Insilico has also launched PreciousGPT, which employs multimodal transformer-based transfer learning and feature importance analysis to analyse omics data and enhance the discovery of targets that may reverse or accelerate biological age. The company has also built “Life Models”, such as Precious3GPT, a multimodal multiomics, multispecies, multi-tissue, multi-function transformer model that is capable of predicting age and supporting the discovery of new drugs.

Whilst longevity research is still in its infancy, the field is wide open for exploration and there are considerable opportunities to develop treatments for age-related diseases through the depletion of senescent cells, stem cell therapy, and antioxidative and anti-inflammatory treatments. 

“Over the next decade, we can expect the pharmaceutical industry to make significant strides in addressing age-related chronic diseases, which are not inevitably untreatable,” predicts Zhavoronkov.