Cellular senescence is a stress response mechanism activated upon a variety of stimuli, external or internal to the cell. On a transient basis, senescence preserves homeostasis, as it facilitates removal of damaged and/or dysfunctional cells by the immune system. However, if senescent cells are not promptly removed, they can accumulate in tissues and organs over time, fostering aging and the development of various age-related disorders, including cancer.
The field of senolytics, dealing with drugs that eliminate these cells in order to alleviate their adverse effects (senolysis), has been rapidly expanding in the last two decades. Yet, currently available senolytics are repurposed drugs that exhibit significant undesirable side-effects.
Capitalizing on a unique feature of senescent cells that we identified, namely the accumulation of lipofuscin (dark matter), we developed an innovative senolytic platform for targeted senolysis with minimal systemic toxicity.

Dr Gorgoulis is Professor and Director at the Dept of Histology–Embryology, Faculty of Medicine, National Kapodistrian Univ of Athens, Greece. He is also Chair and Professor of Clinical Molecular Pathology, Ninewells Hospital and Medical School, Univ of Dundee, UK; Adjunct Prof in the Biomedical Research Foundation, Academy of Athens; Honorary Prof at Institute of Cancer Sciences, Univ of Manchester, UK; and a member in European Molecular Biology Organization (EMBO).

Telomere shortening was the first demonstrated cause of cell aging, also known as cellular senescence. The causative engagement of telomeres was later extended to long but damaged telomeres. It is now well established that short and/or damaged telomeres are associated, often causatively, with several age-related diseases and aging itself.
We recently develop novel innovative RNA therapy-based tools able to reduce the consequences of telomere dysfunction (that is: DNA damage response (DDR) activation at telomeres). This allowed us to determine the contribution of telomere dysfunction in a number of animal models of human diseases. We will demonstrate how selective DDR inhibition at telomeres represent an effective therapy in animal models of telomere-biology diseases, including evidence of lifespan extension in wild-type animals.
In addition we will discuss how telomere clocks interact, or not, to other clocks measuring aging, including those based on DNA methylation changes.

1. https://www.nature.com/articles/s41556-022-00842

2. https://www.nature.com/articles/ncb2466

3. https://www.nature.com/articles/nature02118

I am a molecular and cell biologist and I have devoted my professional life to understand the critical biological mechanisms underlying aging and cancer. 
I have been awarded the European Research Council (ERC) advanced grant twice and am a member of the European Molecular Biology Organization (EMBO).
Together with my group we have developed an inhibitor of cellular aging based on RNA therapeutics and have validated it in several in vivo models of human diseases.

Senescence is induced by such insults as replicative stress, DNA damage, radiation, chemotherapy, pathogens (e.g., HPV, HIV), or oncogenes in almost any cell type, including cancer cells. It entails replicative arrest, a senescence-associated secretory phenotype (SASP), spread of senescence, and resistance to cell death. Senescent cells (SC) are normally removed by the innate and adaptive immune system. Preventing senescence can lead to cancer, but persisting SCs that evade immune clearance, including cancer therapy-induced SCs (TIS), can undergo mutational events and escape senescence as therapy-resistant cancer cells. SCs in cancers can produce growth factors and cause fibrosis, microvascular impairment, and immune dysfunction, contributing to cancer relapse and growth. Senolytics selectively kill TIS with a pro-apoptotic SASP, but not all TIS. A new drug class, senosensitizers, allows senolytics to kill TIS that are not-pro-apoptotic, potentially enhancing cancer treatment outcomes.

1. Tchkonia, T., Kritchevsky, S., Kuchel, G.A., Kirkland, J.L. NIA Translational geroscience network: An infrastructure to facilitate geroscience-guided clinical trials. J Am Geriatr Soc. 2024 May;72(5):1605-1607. doi: 10.1111/jgs.18901. Epub 2024 Apr 22. PMCID: PMC11090706. PMID: 38650350.
2. Wyld, L., Bellantuono, I., Tchkonia, T., Morgan J., Turner, O., Foss, F., George, J., Danson, S., Kirkland, J.L. Senescence and cancer: A review of clinical implications of senescence and senotherapies. Cancers (Basel). 2020 Jul 31;12(8):E2134. doi: 10.3390/cancers12082134. PMID: 32752135.
3. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A., Ding, H., Giorgadze, N., Palmer, A.K., Ikeno, Y., Borden, G., Lenburg, M., O'Hara, S.P., LaRusso, N.F., Miller, J.D., Roos, C.M., Verzosa, G.C., LeBrasseur, N.K., Wren, J.D., Farr, J.N., Khosla, S., Stout, M.B., McGowan, S.J., Fuhrmann-Stroissnigg, H., Gurkar, A.U., Zhao, J., Colangelo, D., Dorronsoro, A., Ling, Y.Y., Barghouthy, A.S., Navarro, D.C., Sano, T., Robbins, P.D., Niedernhofer, L.J., Kirkland, J.L. The Achilles' heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell 14:644-658, 2015. PMID: 25754370.

Dr. Kirkland studies the contribution of aging processes, particularly cellular senescence, to disorders across the lifespan and development of gerotherapeutics that target aging mechanisms to delay, prevent, alleviate, or treat the conditions that cause the bulk of disability, mortality, and health expenditures. He discovered senolytics and published the first composite biomarker score of senescent cell burden in humans and the first clinical trials of senolytic drugs.

A common feature of older organisms is the accumulation of senescent cells – cells that have irreversibly lost the capacity to undergo replication. Senescent cells develop the Senescence-Associated Secretory Phenotype (SASP), which include many tissue remodeling and pro-inflammatory factors. Senescent cells are intermittently present during embryogenesis and in young organisms, where they favor tissue repair and help to recover from acute injuries. On the contrary, many groups, including ours, have shown the senescent cells accumulate and persist in aging tissues. Significantly, these persistent senescent cells can drive low-grade chronic inflammation, and their genetic or pharmacological elimination is sufficient to delay a number of diseases and to improve health span. Here, I will discuss the mechanisms by which senescent cells can either promote tissue repair and remodeling or aging and dysfunction, and the potential of modulating senescent cells to improve health.

1. Nehme J, Mesilmany L, Varela-Eirin M, Brandenburg S, Altulea A, Lin Y, Gaya da Costa M, Seelen M, Hillebrands JL, van Goor H, Saab R, Akl H, Prevarskaya N, Farfariello V, Demaria M. Converting cell death into senescence by PARP 1 inhibition improves the recovery from acute oxidative injury. 2024. Nature Aging. 4:771-782
2. Kohli J, Fitsiou E, Ge C, Wang B, Brandenburg SM, Diercks GFH, Faller WJ, Demaria M. Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression. 2022. Nature Communications. 13: 7923
3. Vliet T, Wang B, Varela-Eirin M, Borghesan M, Brandenburg S, Evangelou K, Franzin R, Seelen M, Gorgoulis V, Demaria M. Physiological hypoxia restrains the Senescence-Associated Secretory Phenotype (SASP) via AMPK-mediated mTOR suppression. 2021. Molecular Cell. 81:2041-2052

Marco Demaria is a Professor of Cellular Ageing at the Medical Faculty of the University of Groningen (RUG) and the Group leader of laboratory of Cellular Senescence and Age-related Pathologies at the European Research Institute for the Biology of Ageing (ERIBA, Groningen, Netherlands). He obtained his PhD in Molecular Medicine at the University of Torino, Italy, and trained as postdoc in the laboratory of prof. Judith Campisi at the Buck Institute for Research on Aging, California USA. His research is focused towards understanding the role of cellular senescence in different physiological and pathological contexts with the goal to identify novel interventions to extend healthy longevity. His laboratory covers fundamental, translational and clinical aspects, and is funded by several intramural and extramural agencies. Since 2023, Prof. Demaria also serves as the Director of the Mechanisms of Health, Ageing and Disease (MoHAD) of the University Medical Center Groningen. Additionally, Prof. Demaria is the President of the International Cell Senescence Association and Editor in Chief of the journal Aging-US.

Senescent cells and their robust secretome mediate age-related changes in the structure and function of multiple tissues, including skeletal muscle. Correspondingly, there is great interest in identifying strategies to either eliminate (senolytics) or alter the behavior (senomorphics) of senescent cells. This seminar will briefly highlight the evidence for cellular senescence as a mediator of skeletal muscle loss in the context of aging and cancer and showcase the effects of new pharmacological senolytic and senomorphic compounds in preclinical models. Moreover, it will demonstrate that cornerstones of healthy aging, including exercise and diet, influence biomarkers of cellular senescence in humans.

1. Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia.
   Englund DA, Jolliffe AM, Hanson GJ, Aversa Z, Zhang X, Jiang X, White TA, Zhang L, Monroe DG, Robbins PD, Niedernhofer LJ, Kamenecka TM, Khosla S, LeBrasseur NK.JCI Insight. 2024 Jan 23;9(2):e169512. doi: 10.1172/jci.insight.169512.PMID: 38051584 Free PMC article.
   
   
2. Biomarkers of Cellular Senescence Predict the Onset of Mobility Disability and Are Reduced by Physical Activity in Older Adults.
   Fielding RA, Atkinson EJ, Aversa Z, White TA, Heeren AA, Mielke MM, Cummings SR, Pahor M, Leeuwenburgh C, LeBrasseur NK.J Gerontol A Biol Sci Med Sci. 2024 Mar 1;79(3):glad257. doi: 10.1093/gerona/glad257.PMID: 37948612 Free PMC article. Clinical Trial.
   
   
3. Characterization of cellular senescence in aging skeletal muscle.
   Zhang X, Habiballa L, Aversa Z, Ng YE, Sakamoto AE, Englund DA, Pearsall VM, White TA, Robinson MM, Rivas DA, Dasari S, Hruby AJ, Lagnado AB, Jachim SK, Granic A, Sayer AA, Jurk D, Lanza IR, Khosla S, Fielding RA, Nair KS, Schafer MJ, Passos JF, LeBrasseur NK.Nat Aging. 2022 Jul;2(7):601-615. doi: 10.1038/s43587-022-00250-8. Epub 2022 Jul 15.PMID: 36147777 Free PMC article.

Nathan LeBrasseur, PT, PhD, holds the Noaber Foundation Professorship in Aging Research and has appointments in the Department of Physical Medicine and Rehabilitation and the Department of Physiology and Biomedical Engineering at Mayo Clinic. Dr. LeBrasseur is the Director of the Robert and Arlene Kogod Center on Aging and the Co-Director of the Paul F. Glenn Center for Biology of Aging Research at Mayo Clinic. He is the recent chair of the NIH Cellular Mechanisms in Aging and Development Study Section. Dr. LeBrasseur’s research team conducts translational “bench-to-bedside” research on strategies to improve physical function, metabolism, and resilience in the face of aging and disease. His latest work has centered on cellular senescence, a fundamental mechanism of aging, and interventions to counter this process to extend healthspan. Dr. LeBrasseur has received the Glenn Award for Research in Biological Mechanisms of Aging, the Nathan W. Shock Award Lecture from the National Institute on Aging, and the Vincent Cristofalo Rising Star Award in Aging Research from the American Federation for Aging Research. He is a Fellow of the Gerontological Society of America.