Our group combines mathematical modelling, large-scale biomedical data and experiments, to understand human physiology, aging and disease. We are physicists, biologists, computer scientists and MDs working together to form the basic equations of hormone circuits, antibiotics, autoimmunity, cancer, mood disorders and age-related diseases. Our style emphasizes teaching good communication skills, listening and having fun being creative while going together into the unknown.
Raz M., Milo T., Glass D. S., Mayo A. & Alon U.
(2024)
iScience.
27,
9,
110625.
Endocrine glands secrete hormones into the circulation to target distant tissues and regulate their functions. The qualitative relationship between hormone-secreting organs and their target tissues is well established, but a quantitative approach is currently limited. Quantification is important, as it could allow us to study the endocrine system using engineering concepts of optimality and tradeoffs. In this study, we collected literature data on 24 human hormones secreted from dedicated endocrine cells. We find that the number of endocrine cells secreting a hormone is proportional to the number of its target cells. A single endocrine cell serves approximately 2,000 target cells, a relationship that spans 6 orders of magnitude of cell numbers. This suggests an economic principle of cells working near their maximal capacity, and glands that are no bigger than they need to be.
Majewska J., Agrawal A., Mayo A., Roitman L., Chatterjee R., Sekeresova Kralova J., Landsberger T., Katzenelenbogen Y., Meir-Salame T., Hagai E., Sopher I., Perez-Correa J. F., Wagner W., Maimon A., Amit I., Alon U. & Krizhanovsky V.
(2024)
Nature Cell Biology.
26,
8,
p. 1336-1345
The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.
Understanding the mechanisms of geroprotective interventions is central to aging research. We compare four prominent interventions: senolysis, caloric restriction, in vivo partial reprogramming, and heterochronic parabiosis. Using published mice transcriptomic data, we juxtapose these interventions against normal aging. We find a gene expression program common to all four interventions, in which inflammation is reduced and several metabolic processes, especially fatty acid metabolism, are increased. Normal aging exhibits the inverse of this signature across multiple organs and tissues. A similar inverse signature arises in three chronic inflammation disease models in a non-aging context, suggesting that the shift in metabolism occurs downstream of inflammation. Chronic inflammation is also shown to accelerate transcriptomic age. We conclude that a core mechanism of geroprotective interventions acts through the reduction of inflammation with downstream effects that restore fatty acid metabolism. This supports the notion of directly targeting genes associated with these pathways to mitigate age-related deterioration.
