Chapter 184
Changing Aging — 21
The search for the youth factor has also been undertaken through the cerebrospinal fluid, since transferring young CSF to old mice provides similar benefits as plasma infusions. Fibroblast growth factor 17 (Fgf17) was sufficient on its own to achieve the effect. Most of these studies have been conducted in mice, but a more recent one taking young plasma from pigs infused to rats also showed similar benefits with reversal of epigenetic clocks.
Studies in people are scant. A small randomized trial of plasma donated by young people for nine patients with Alzheimer’s backed up safety but without signs of benefit. Without knowing the specific factors or potential side effects, the strategy of diluting (by 60–70%) blood proteins through plasmapheresis (therapeutic plasma exchange, TPE) appears to be the safest way to test the hypothesis in three participants undergoing three rounds of TPE out to one year. This provided evidence of reduced inflammation, inflammaging, and less protein biomarkers linked to neurodegeneration and cancer.
Despite the lack of efficacy or safety in people, companies and clinics have been offering young plasma infusions and plasmapheresis for their putative antiaging effects. Ambrosia offered plasma from people aged sixteen to twenty-five years for $8,000 a liter. In 2019, the FDA issued a warning about young donor plasma infusions that included language that “some patients are being preyed upon by unscrupulous actors.” Nonetheless, there are still companies selling young plasma infusions, and TPE is still being offered by Next Health for $10,000, the Young Blood Institute, Maxwell Clinic, and many other companies. It’s important to emphasize that besides the expense and lack of any proof for benefit, there are significant hazards of plasma infusions and plasmapheresis.
The young to old mice rejuvenation benefits extend beyond blood and cerebrospinal fluid to the gut microbiome, whereby fecal microbial transplants showed improvement in gut, eye, and brain function in aged mice, which all went the opposite direction with transplants from old to young mice.
Enough about old blood; it’s time to move onto old, zombie senescent cells and how to get rid of them and avoid their deleterious impact. Back in 2015, my colleagues at Scripps Research published, in collaboration with Mayo Clinic researchers, a study of how well a combination of senolytics can kill senescent cells in mice. There is now abundant evidence of benefit for this intervention in mice. The first-generation senolytic drugs include the tyrosine kinase inhibitor dasatinib, an approved drug for treating leukemia, and naturally occurring flavonoid plant metabolites such as quercetin and fisetin. The senescent cells are resistant to cell death, apoptosis; to address this, another group of drugs, BCL-2 inhibitors like navitoclax and other pro-apoptotics, are in this group. Second-generation drugs include engineered (CAR-T) cells targeting senescent cells and drug or nanoparticle approaches to improve waste disposal of the senescent cells, such as glutaminase 1 (GLS1) or others targeting beta-galactosidase. Unlike the young blood story, there are many ongoing early phase (½) clinical trials and programs testing senolytics, mostly with the first-generation compounds and often in combination. There are ongoing trials in pulmonary fibrosis, kidney disease, Alzheimer’s, osteoarthritis, sepsis, frailty, and diabetic macular edema. Early, small trials have indicated proof of clearing senescent cells with dasatinib and quercetin in diabetic kidney disease and idiopathic pulmonary fibrosis, but failed to provide clinical benefit in knee osteoarthritis or bone metabolism in postmenopausal women.