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Institute for Physiology and Pathophysiology
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Metabolism and Aging.

People today are experiencing significantly longer lifespans compared to a century ago, thanks to advancements in modern science. However, this achievement is accompanied by a notable increase in age-related diseases. This growing disparity between the duration of good health (healthspan) and overall lifespan prompts a crucial inquiry: can we not only extend life but also enhance its quality?

Previous hypotheses, including heightened somatic mutation rates and telomerase dynamics, don't appear to be sole determinants of aging. Conversely, the surge in age-linked diseases corresponds with a decline in the body's overall metabolic rate. Furthermore, alongside epigenetic alterations, metabolic rewiring is recognized as a hallmark of cellular aging. Strategies like caloric restriction can postpone the onset of age-related illnesses, albeit they are often extreme and challenging to maintain. Ideally, we aim to postpone aging and enhance healthspan by pinpointing crucial metabolic pathways. Yet, the specific pathways or factors to target remain elusive.

Which metabolic pathways can we manipulate to promote extended healthspan in humans?

scheme cikes Figure 1. The relationship between whole-body metabolic rate and the incidence of age-related diseases. At around age 60, there is a significant decrease in the total metabolic rate, which represents the sum of the metabolic activities occurring in human cells and tissues. Concurrently, there is a sharp exponential increase in the prevalence of most age-related diseases, leading to a reduction in human healthspan.

We propose that pivotal metabolic elements can be manipulated to revitalize the entire body and boost human healthspan. Recognizing that each organ and cell type possesses distinct metabolic needs and vulnerabilities, a universal treatment approach is impractical. Therefore, we advocate for a precision medicine approach tailored to individual tissues.

Our primary research objective is to identify these critical metabolic factors essential for healthspan. Leveraging our extensive expertise in aging1,2 and metabolic studies at both subcellular, tissue and whole-body levels3–6, we integrate various advanced technologies and adopt a holistic methodology to address one of biology's foremost unanswered questions and humanity's significant health and economic challenges.

Selected Literature:

1. Cikes, D. et al. Gpcpd1–GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism. Nat Aging 4, 80–94 (2024).

2. Keshmiri, H. Cikes, D.et al. Brillouin light scattering anisotropy microscopy for imaging the viscoelastic anisotropy in living cells. Nat Photonics (2024) doi:10.1038/s41566-023-01368-w.

3. Cikes, D. et al. PCYT2-regulated lipid biosynthesis is critical to muscle health and ageing. Nat Metab (2023) doi:10.1038/s42255-023-00766-2.

4. Vietor, I.*, Cikes, D.et al. The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15). Elife 12, (2023). (* equal contribution)

5. Orthofer, M. et al. Identification of ALK in Thinness. Cell (2020) doi:10.1016/j.cell.2020.04.034.

6. Cronin, S. J. F. et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 563, (2018).