From lab to longevity: CCM Biosciences’ enzyme activators that reverse mitochondrial aging

In a landmark longevity study, scientists at the biopharmaceutical company CCM Biosciences have discovered enzyme activators that restore a “previously undruggable” mitochondrial regulator of cellular energy production to youthful activity levels.

These enzyme-stimulating compounds show promise for cellular rejuvenation and treating age-related diseases, the company highlights. However, their development has been challenging due to reliance on allosteric modulation — a mechanism feasible in less than 10% of proteins.

The discovered compounds fully restore the enzyme’s activity to youthful levels and hold significant potential for clinical development to address a range of age-related disorders, including Alzheimer’s disease, Parkinson’s disease, cardiovascular conditions and metabolic diseases.

“The discoveries by CCM Biosciences pertaining to the design of drug candidates that can activate the major mitochondrial pathways regulated by sirtuins, along with the clinical development plan for evaluation of efficacy as well as safety of these drug candidates, revitalize this area of drug development,” says Dr. Michael Pollak, professor of medicine, oncology and pharmacology at McGill University, Canada.

“Efforts have been underway for decades to activate signaling pathways regulated by sirtuins to combat age-related disorders, but prior efforts have encountered significant hurdles.”

Enzyme-facilitated cellular rejuvenation

Competition platform XPRIZE Foundation recently announced its largest funding in history for a seven-year plan to rejuvenate cells, evidencing rising investor activity in the longevity arena. CCM highlights that the ability to add just one year of healthy life to the global population is estimated to be worth over US$10 trillion.

The company says many chronic, age-related disorders could be mitigated by enhancing the activity of enzymes that regulate biochemical signaling pathways. However, despite this intense global interest, it notes finding enzyme-activating compounds has been challenging, particularly because they typically rely on a mechanism called allosteric modulation, a process that is known to be feasible in less than 10% of proteins.

A team of scientists at CCM and its affiliated R&D center Chakrabarti Advanced Technology expanded the scope of enzyme activation beyond allosteric modulation by introducing new physical principles for enzyme activation.

The scientists successfully applied computational and experimental design methods to identify new compounds that “dramatically enhance” the activity of previously undruggable enzyme Sirtuin-3 (SIRT3), which is crucial in regulating human aging.

Their research is published in Physical Review X. The proposed compounds are also undergoing animal testing in mice for age-related disorders, including infertility, where they have “outperformed” both NAD+ (nicotinamide adenine dinucleotide) supplements and other sirtuin activators. 

Billions of dollars have been invested over the past two decades in efforts to upregulate sirtuin enzymes due to their role in regulating healthspan and lifespan.Efforts to upregulate sirtuin enzymes

Billions of dollars have been invested over the past two decades in efforts to upregulate sirtuin enzymes due to their role in regulating healthspan and lifespan.

For instance, the biotechnology company Sirtris Pharma, founded based on the work of longevity researchers from Harvard and MIT, was bought by GlaxoSmithKline for US$720 million.

However, CCM notes that Sirtris’ development of drug candidates, which were allosteric activators, was subsequently terminated due to the observation that they only functioned with a limited number of substrates for one of the seven sirtuin enzymes.

“Due to the difficulty of identifying activators that upregulate more sirtuin enzymes under more physiologically relevant conditions, companies such as Elysium Health (MIT) had largely abandoned the efforts to develop targeted sirtuin activators and instead turned to marketing nutraceuticals to increase sirtuin activity,” details the company.

“Notably, SIRT3, the major mitochondrial sirtuin enzyme, plays a critical role in determining human healthspan and lifespan through the regulation of mitochondria — the energy production powerhouses of cells that decline with age — but was considered undruggable due to lack of a known allosteric site.”

CCM underscores that its recently discovered lead compounds greatly increase the sensitivity of SIRT3 to the essential metabolic cofactor NAD+, whose levels decrease with age and play a major role in the onset of many age-related diseases.

While the researchers had identified protein mutations in sirtuins that could increase the sensitivity of a related enzyme SIRT1 to NAD+, they were not successful in designing druglike compounds that could achieve this effect.

The CCM compounds fully recovered the activity of SIRT3 in the face of NAD+ levels decreasing by a factor of two, as observed in old age. The scientists have also demonstrated that their compounds increase SIRT3 activity in the face of declining NAD+ for multiple cell lines employed in aging studies.

Market for anti-aging therapies

In recent years, CCM highlights investment in therapeutic interventions for age-related disorders has surged, with invested capital in 2024 exceeding US$5 billion. Notable examples include Calico (an Alphabet company) and Altos Labs, each of which has received over US$3 billion in funding.

However, CCM notes very few proprietary first-in-class drug candidates have advanced to clinical trials for efficacy against age-related disorders. In contrast, the drug programs of CCM for age-related disorders are entering clinical trials for efficacy in 2025.

Nutrition Insight recently examined the top nutrition trends poised to steer the course of supplement formulation in 2025, featuring insights from key industry experts, with the longevity theme rising in prominence.

In related news, David Beckham’s IM8 supplement brand, co-founded with Prenetics, recently sent specially designed 3D organoids — miniature, simplified versions of human tissues — into space to study accelerated aging, leveraging microgravity’s unique environment that will speed up this process.