The role of p16High immune subsets in the regulation of acute tissue damage as well as their role in aging. We have found that that p16High immune cells play a key role in establishing disease tolerance. We found that the FDA- approved BNT162b2 mRNA COVID-19 vaccine is a potent and rapid inducer of p16High immune subsets both in mice and men. In turn, p16High immune cells were indispensable for counteracting different lethal conditions, including LPS- induced sepsis, acute SARS-CoV-2 infection and ionizing irradiation. Mechanistically, we propose that activation of TLR7 or a low physiological activity of STING is sufficient to induce p16High immune subset that, in turn, establishes a low adenosine environment and disease tolerance. Furthermore, containing these signals within a beneficial range by deleting MDA5 that appeared sufficient to maintain a low activity of STING, induces p16High immune cells and delays organ deterioration upon aging with improved healthspan. Our data highlight the beneficial role of p16High immune subsets in establishing a low adenosine environment and disease tolerance. A part of this work is currently under review. As additional and important aspect of this project, we investigate the role of p16High immune subsets in controlling response to vaccination. In additional, we are looking how the presence of p16High cells could impact the in vivo rejuvenation using 4 Yamanaka factors protocol.

The role of p16High cells in the eye with its relevance to diabetes-induced retinopathy. We have found a very significant build-up of p16High cells in the retina with aging as well as in diabetic mice. The significance of these changes are currently under investigation.