Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age.

We hypothesize that altered intensities of a few morphogenic pathways account for most/all the phenotypes of aging. Investigating this has revealed a novel approach to rejuvenate multiple mammalian tissues by defined pharmacology. Specifically, we pursued the simultaneous youthful in vivo calibration of two determinants: TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age. The dose of Alk5 inhibitor (Alk5i) was reduced by 10-fold and the duration of treatment was shortened (to minimize overt skewing of cell-signaling pathways), yet the positive outcomes were broadened, as compared with our previous studies. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. Interestingly, the combination also diminished the numbers of cells that express the CDK inhibitor and marker of senescence p16 in vivo. Summarily, simultaneously re-normalizing two pathways that change with age in opposite ways (up vs. down) synergistically reverses multiple symptoms of aging.

Key Age-Imposed Signaling Changes That Are Responsible for the Decline of Stem Cell Function.

This chapter analyzes recent developments in the field of signal transduction of ageing with the focus on the age-imposed changes in TGF-beta/pSmad, Notch, Wnt/beta-catenin, and Jak/Stat networks. Specifically, this chapter delineates how the above-mentioned evolutionary-conserved morphogenic signaling pathways operate in young versus aged mammalian tissues, with insights into how the age-specific broad decline of stem cell function is precipitated by the deregulation of these key cell signaling networks. This chapter also provides perspectives onto the development of defined therapeutic approaches that aim to calibrate intensity of the determinant signal transduction to health-youth, thereby rejuvenating multiple tissues in older people.

A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood.

Heterochronic parabiosis rejuvenates the performance of old tissue stem cells at some expense to the young, but whether this is through shared circulation or shared organs is unclear. Here we show that heterochronic blood exchange between young and old mice without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis. Investigating muscle, liver and brain hippocampus, in the presence or absence of muscle injury, we find that, in many cases, the inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects. We also explore mechanistic explanations, including the role of B2M and TGF-beta. We conclude that, compared with heterochronic parabiosis, heterochronic blood exchange in small animals is less invasive and enables better-controlled studies with more immediate translation to therapies for humans.