Scientists restore ‘youthful’ enzyme activity to fight aging

Innovative therapies revive a once-intractable regulator of mitochondrial aging through a revolutionary enzyme activation mechanism.

Researchers at CCM Biosciences, Inc. have harnessed a novel biophysical mechanism of enzyme activation to discover and characterize breakthrough enzyme activators for a previously untargetable master regulator of cellular energy production.

These first-in-class compounds restore enzyme activity to levels comparable to those in young cells, offering substantial potential for clinical applications in the treatment of age-related disorders such as

” data-gt-translate-attributes=”({“attribute=”” tabindex=”0″ role=”link”>AlzheimerParkinson’s disease, cardiovascular diseases and metabolic disorders.

Improving healthy life expectancy by even one year is estimated to have a global economic value of more than $10 trillion. In line with this potential, the largest XPRIZE in history recently launched a seven-year initiative focused on cellular rejuvenation.

Many age-related chronic diseases can be treated by stimulating the activity of enzymes responsible for regulating critical biochemical signaling pathways. Despite worldwide attention to this area, the identification of enzyme activators remains difficult due to their reliance on allosteric modulation, a viable mechanism in less than 10% of proteins.

Going beyond traditional enzyme activation

Recently, a team of scientists from CCM Biosciences 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 and applying it with success of computational and experimental design methods based on these principles to identify new compounds. which considerably improve the activity of the previously essential Sirtuin-3 (SIRT3) enzyme, which plays a central role in the regulation of human aging. This study was published in Physical examinationthe flagship journal of the American Physical Society (APS), October 22, 2024.

Billions of dollars have been invested over the past two decades in efforts to upregulate sirtuin enzymes because of their role in regulating health and lifespan. The biotechnology company Sirtris Pharma, founded on the work of longevity researchers from Harvard and

” data-gt-translate-attributes=”({“attribute=”” tabindex=”0″ role=”link”>MITwas acquired by GlaxoSmithKline for $720 million, but development of its drug candidates, which were allosteric activators, was subsequently halted due to the observation that they only worked 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) have largely abandoned efforts to develop targeted sirtuin activators and have instead turned to marketing nutraceutical products to increase sirtuin activity.

Unlocking the potential of SIRT3 activation

Notably, SIRT3, the major mitochondrial sirtuin enzyme, plays a critical role in determining human health and lifespan through the regulation of mitochondria – the energy-producing powerhouses of cells that decline with age – but was considered unusable due to the lack of a known allosteric site. . Lead Compounds Newly Discovered by CCM Scientists Significantly Increase SIRT3 Sensitivity to the Essential Metabolic Cofactor NAD⁺ (nicotinamide adenine dinucleotide), levels of which decrease with age and play a major role in the onset of many age-related diseases. While researchers had identified protein mutations in sirtuins that could increase the sensitivity of a related enzyme SIRT1 to NAD⁺they failed to design drug-like compounds capable of achieving this effect.

CCM compounds fully rescued SIRT3 activity against NAD⁺ levels decreasing by a factor of two, as observed in older people. The scientists also showed that their compounds increase SIRT3 activity in the face of NAD decline.⁺ for several cell lines used in aging studies. The proposed compounds are also in animal testing in mice for age-related disorders, including infertility, where they outperformed both NAD⁺ supplements and other sirtuin activators.

In recent years, investment in therapeutic interventions for age-related disorders has increased, with capital invested in 2024 exceeding $5 billion. Notable examples include Calico (an Alphabet company) and Altos Labs, which each received over $3 billion in funding.
However, very few proprietary, first-in-class drug candidates have undergone clinical trials to evaluate their effectiveness in combating age-related disorders. In contrast, CCM Biosciences’ drug programs for age-related disorders will enter clinical efficacy trials in 2025.

Dr. Michael Pollak, professor of medicine, oncology and pharmacology at McGill University and an expert in clinical trials for age-related disorders and the biochemistry of signaling pathways regulated by sirtuin, says that “efforts have been underway for decades to activate signaling pathways. regulated by sirtuins to combat age-related disorders, but previous efforts have faced significant obstacles. CCM Biosciences’ discoveries relating to the design of drug candidates capable of activating key mitochondrial pathways regulated by sirtuins, as well as the clinical development plan for evaluating the efficacy and safety of these drug candidates , are revitalizing this area of ​​drug development.

Reference: “Discovery and computational characterization of SIRT3-activating compounds that fully recover catalytic activity under NAD+ Depletion” by Xiangying Guan, Rama Krishna Dumpati, Sudipto Munshi, Santu Chall, Rahul Bose, Ali Rahnamoun, Celina Reverdy, Gauthier Errasti, Thomas Delacroix, Anisha Ghosh and Raj Chakrabarti, October 22, 2024, Physical examination.
DOI: 10.1103/PhysRevX.14.041019