“Previously, the only biochemical pathway that was known to be activated by metformin was the AMPK pathway, which Shaw discovered stalls cell growth and changes metabolism when nutrients are scarce, as can occur in cancer. But the scientists believed more pathways than AMPK might be involved.

The scientists developed a novel screening platform to examine kinases, the proteins that transfer phosphate groups, which are critical on/off switches in cells and can be rapidly flipped by metformin. Using this technology, the researchers were able to decode hundreds of regulatory “switch-flipping” events that could affect healthy aging.”

https://medicalxpress.com/news/2019-12-diabetes-drug-unexpected-broad-implications.html

“Ageing and many diseases are partly driven by the accumulation of damaged cells that no longer divide. It emerges that these senescent cells can be eradicated in mice using a drug that interferes with the activity of the protein FOXO4.

If cells incur too much damage, they undergo either a self-elimination process known as apoptosis or a self-disabling process called senescence. Senescent cells can be long-lived, and so accumulate in aged and damaged organs¹. The elimination of senescent cells is known^2,3,4,5,6 to increase healthy lifespan and reduce the severity of age-related diseases in mice. Writing in Cell, Baar et al.⁷ expand our understanding of this phenomenon. They report that senescent cells depend on the transcription factor forkhead box protein O4 (FOXO4) for their survival, and show in mouse models that both age-associated defects and tissue dysfunction caused by chemotherapy can be reversed by pharmacologically perturbing the function of this protein.

Senescent cells forcibly block their own capacity to proliferate while programming themselves to secrete signalling molecules — a phenomenon known as the senescence-associated secretory phenotype (SASP). It has been proposed^8,9 that the normal function of the SASP is to restore tissue function in two ways: first, by stimulating less-damaged neighbouring cells to engage in tissue repair; and second, by attracting inflammatory cells to eliminate senescent cells and turn off SASP-mediated signals. However, this restorative process may fail when the extent, duration or frequency of damage exceeds repair capacity, or when reparative and inflammatory cells become unresponsive to the effects of the SASP. The end result is an aberrant accumulation of senescent cells that, contrary to their initial purpose, aggravate tissue dysfunction.” Serrano, M. Tools to eliminate senescent cells. Nature545, 294–295 (2017) doi:10.1038/nature22493

https://rdcu.be/bX5uQ

Nicotinamide adenine dinucleotide (NAD), the cell’s hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan.

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. – PubMed – NCBI

https://www.sciencedaily.com/releases/2019/11/191113101845.htm