Changing Aging — 20

For an alternative to growth hormone for antiaging immune cells, partial epigenetic reprogramming with the Yamanaka factors (OKSM) plus two accessory factors (LIN28 and NANOG) was undertaken in various types of cells in culture, including immune cells, to reverse epigenetic and inflammatory signatures. But this has not yet been tested in experimental models or humans. In the meantime, this may be used outside the body to rejuvenate engineered T cells used for cancer therapy.

There is an exceptionally large number of companies betting big on this strategy of partial epigenetic reprogramming, which includes not only Altos but also New Limit, Rejuvenate Bio, Life Biosciences, YouthBio Therapeutics, Shift Bioscience, Retro Biosciences, and several others.

Any search for a fountain of youth is bound to consider young blood. For more than two decades, we’ve known about its magic. Initial experiments involved the surgical union of two mice (parabiosis), one old and one young (heterochronic), with shared blood supply, providing evidence for improved multiorgan function in the aged animal and deterioration in the young one. When parabiosis was sustained for three months, there was evidence of extended lifespan, marked reversal of epigenetic clocks, improved physical function, and rejuvenation by tissue omic signatures, which lasted months after the mice were detached from each other. The results have not yet been replicated, but another set of independent experiments refuted the benefit. Assuming the salutary and sustained effects hold up for parabiosis, although the results are intriguing, we’re not going to surgically connect humans, so we need a more practical path, no less a hunt for the explanation of what is providing the benefit.

Systemic administration of young plasma (eight times over twenty-four days) to aged mice yielded improved cognition and memory, marked increase in new neurons (neurogenesis), and strengthened connections of hippocampus circuit neurons (known as synaptic plasticity), mimicking what was achieved via parabiosis. When half the plasma in old mice was replaced by a saline-albumin infusion, via a single thirty-minute procedure, there was replication of multiorgan benefits including cognition, less inflammation, reduced liver fibrosis, and muscle repair. That raised the potential that rejuvenation of old mice was more of a function of diluting proteins in old blood. Other hints for what was driving the benefit came from the blood of exercised animals. Administering the plasma from exercised aged mice to sedentary counterparts improved cognition and hippocampus synaptic plasticity. A blood factor derived from the liver (Gpld1) was a mediator.

But the pro-youthful factor(s) in young mice blood has/have yet to be nailed down. Studies have raised many candidates, such as growth differentiation factor 11 (GDF11), osteocalcin, Klotho, platelet factor 4 (PF4), small extracellular vesicles, and a long list of others. When Klotho was given to nonhuman primates at low dose with a single injection, it enhanced memory and cognition. Regarding PF4, direct administration simulated the benefits of young plasma for rescuing cognition in aged mice and reducing brain inflammation. Proprietary plasma factors are being tested in clinical trials for Parkinson’s disease with cognitive impairment and mild to moderate Alzheimer’s disease.