A remarkable discovery has shifted the narrative on aging: proline, a simple amino acid, is now at the forefront of scientific exploration for rejuvenating aged cells. Far from the realms of science fiction, this finding introduces a new chapter in the study of aging, revealing proline’s potential to reverse time at the cellular level. By introducing proline to cells that have ceased their cycle of division and show signs of aging, researchers have unveiled significant enhancements in cellular functions. This journey into the heart of cellular rejuvenation through proline supplementation opens exciting possibilities for not only extending life but enriching its quality, promising a future where the decline of aging can be significantly mitigated.

In a groundbreaking study that might turn the tide in our ongoing battle against the aging process, Professor Stelios Andreadis from the University at Buffalo, together with a team of researchers, has unveiled how the amino acid proline can breathe new life into aged mesenchymal stem cells (MSCs). This research, detailed in Cell Reports, highlights the potential of proline supplementation to significantly enhance mitochondrial function and promote mitophagy, offering a beacon of hope in reversing the hallmarks of aging.

Mesenchymal stem cells, which have stopped dividing and exhibit signs of aging, were found to have a reduced ability to produce proline, a key player in cellular stress response and bioenergetics. Professor Andreadis elucidated this finding, noting, “Senescent MSCs exhibited severely compromised mitochondrial respiratory chain activity and this was coupled with accumulation of depolarized mitochondria due to defective mitophagy.” This observation underscores the critical role of proline in maintaining cellular vitality.

The researchers embarked on an innovative approach to rejuvenate these cells. By supplementing aged MSCs with proline, they observed a remarkable improvement in mitochondrial function. This process was driven by the activation of AMP-activated protein kinase alpha (AMPK) and the upregulation of Parkin, crucial components in the initiation of mitophagy – the cell’s method of cleaning house by selectively degrading damaged mitochondria. This not only enhanced mitochondrial clearance but also reduced several aging indicators, such as DNA damage and senescence-associated beta-galactosidase activity.

Delving deeper into their methodological approach, the research team provided proline to aged MSCs in a carefully controlled environment, monitoring the effects over time. Professor Andreadis shared, “Proline induces mitophagy by activating AMPK and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism.” This insight is particularly compelling, suggesting a profound impact of seemingly simple molecules on the complex process of aging at the cellular level.

Interestingly, the team also discovered that the positive effects of proline supplementation did not hinge on its breakdown by Proline Dehydrogenase (PRODH), indicating that the presence of proline itself, rather than its metabolites, was key to rejuvenating aged cells. “Knocking down PRODH had no significant effect on the ability of proline to restore mitochondrial function and autophagy flux in senescent cells,” Professor Andreadis remarked, pointing to a sophisticated mechanism at play.

This study not only sheds light on the intricate dance of cellular metabolism in the context of aging but also opens the door to novel therapeutic strategies aimed at mitigating mitochondrial dysfunction associated with aging. The restoration of the regenerative potential of aged stem cells by proline supplementation could lead to breakthrough anti-aging therapies.

Professor Stelios Andreadis and his team have masterfully blended meticulous observation with innovative experimentation, enhancing our understanding of metabolic interventions for combating age-related diseases. In their hands, proline transitions from a molecule of interest to a promising agent for extending healthspan and rejuvenating aged tissues, marking a significant advancement in the science of aging. Their research not only highlights proline’s potential but also ushers in a new chapter in our fight against the aging process.

Journal Reference

Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, et al., “Proline restores mitochondrial function and reverses aging hallmarks in senescent cells,” Cell Reports, vol. 43, no. 113738. DOI: https://doi.org/10.1016/j.celrep.2024.113738

About The Author

Stelios T. Andreadis received his M.S. in Applied Mathematics, and M.S. and Ph.D. degrees in Chemical Engineering from the University of Michigan. He then pursued postdoctoral training at the Center for Engineering in Medicine at Harvard Medical School, where he worked in the areas of gene therapy, tissue engineering and regenerative medicine. Currently he serves as SUNY Distinguished Professor of Chemical and Biological Engineering, Biomedical Engineering and Member of the Center of Excellence in Bioinformatics and Life Sciences at the University at Buffalo, State University of New York. He served as Director of the Stem Cells in Regenerative Medicine (SCiRM) Training Program that was funded by NYSTEM to train students in stem cell biology and bioengineering and applications of stem cells in regenerative medicine (2016-2021). He is the Founding Director of the Cell, Gene, and Tissue Engineering Center (CGTE) that was established two years ago to promote interdisciplinary research and education in these areas. He served as CBE department Chair for two terms from 2012 to 2018.

His research interests span a wide spectrum from fundamental to technological to pre-clinical/translational research. He has made significant research contributions in the areas of stem cell bioengineering; vascular, skin, muscle and gland tissue engineering and regeneration; molecular design of biomaterials; protein and gene delivery, and stem cell senescence and aging. He co-founded a start-up (Angiograft, LLC) to commercialize the cell-free vascular grafts that were developed in his laboratory as arterial replacement grafts for treatment of cardiovascular disease. He has been invited speaker at conferences and many departments around the country and internationally. To date his work has resulted over 145 peer-reviewed publications, 32 conference proceedings, 90 invited presentations and over 300 conference presentations. Publications from his group appeared in top journals including Cell Stem Cell, Nature Communications, Science Advances, Advanced Science, Advanced Functional Materials, Advanced Healthcare Materials, Cell Reports, Stem Cells, Journal of Cell Science, FASEB J., Cardiovascular Research, Molecular Therapy, Journal of Virology, Journal of Investigative Dermatology, Gene Therapy, Biomaterials, Tissue Engineering, Annual Reviews of Biomedical Engineering and others. 

His work has been continuously funded over 20 years from federal, state, and private foundation sources including NIH, NSF, the New York State Stem Cell Fund (NYSTEM), JDRF, the John R. Oishei Foundation and the Whittaker Foundation, totaling over $25 million. Recently, he led a team of UB and RPCI investigators that was awarded a grant from NYSTEM to launch a new Training Program focusing on Stem Cells in Regenerative Medicine (SCiRM).

For his work, he received several awards including the Whitaker Foundation Young Investigator Award (1999), the NSF CAREER Award (2000), the Exceptional Scholar Young Investigator Award (UB, 2003), Exceptional Scholar: Sustained Achievement Award (UB, 2009) and the SUNY Chancellor’s Award for Excellence in Scholarship (2014). He was elected to the College of Fellows of the American Institute for Medical and Biological Engineering (AIMBE, 2009) Biomedical Engineering Society (BMES, 2016), American Institute of Chemical Engineers (AIChE, 2022) and American Association for the Advancement of Science (AAAS, 2022). In 2018, he was promoted to the rank of SUNY Distinguished Professor, the highest rank in the system of SUNY Colleges and Universities.

He has mentored over 115 mentees including 35 Ph.D. and 22 M.S. students, 7 post-doctoral fellows and more than 55 undergraduate researchers. Eight of his former Ph.D. students hold faculty positions at top research Universities (Georgetown, U of Oklahoma, Auburn U, National Institute of Standards and Technology (NIST), U of South Florida, UB, IIT Kanpur, The Capital University of Medical Sciences, Beijing). Others hold post-doctoral positions at top Universities (Harvard, Stanford, Johns Hopkins, U Penn); or research and leadership positions in leading pharmaceutical/biotechnology companies (Merck, Bristol-Myers Squibb, Biogen, Shire Pharmaceuticals, LifeTechnologies, Lyndra Therapeutics, MedImmune, etc.).