Dr.Helen Blau of Stanford University is attempting something seemingly impossible: to treat aging as a disease; to lessen the devastation of old age; to recover strength, muscle mass, and endurance—for people already old.
According to Dr. Blau, a typical person past 50 will lose 10-15% of their strength every decade. But is this inevitable?
Not if a molecule called PGE2 turns out to be helpful.
When Dr. Blau gave PGE2 to old mice, it stimulated muscle stem cells and restored strength, muscle mass and endurance to their aged limbs. They ran faster and longer on the treadmill.
She also discovered a protein that breaks down PGE2, so it will not work. She called the negative protein a gerozyme, an aging associated enzyme, also known as15-PGDH,a prostaglandin degrading enzyme.
The gerozyme accumulates in muscle tissue as we age. Because the gerozyme is present in relatively higher amounts in the elderly, the availability of PGE2decreases, which is problematic for muscle regeneration.
So, the “hero” of aging could be PGE2 (prostaglandin), and the “villain” is the gerozyme 15-PDGH (hydroxyprostaglandin dehydrogenase).
PGE2could make muscles more powerful; 15 PDGH could wither the limbs.
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More information:
For well over a decade now, scientists have been experimenting with “couch potato” drugs that could confer the benefits of exercise without having to flex a muscle. The latest candidate is a small molecule inhibitor impeding the degradation of prostaglandin E2 (PGE2), recently shown to act directly on mature muscle fibers to prevent deleterious molecular changes that arise with aging, according to Helen Blau, professor of microbiology and immunology and director of the Baxter Laboratory for Stem Cell Biology at Stanford University School of Medicine.
In gel form, PGE2 is already being used to induce labor and treat respiratory distress in newborns, says Blau. It now appears that restoring PGE2 later in life could be a way to rejuvenate aging muscles and possibly treat conditions such as age-related muscle atrophy (sarcopenia), Duchenne muscular dystrophy, and other myopathies.
The Stanford researchers previously discovered that PGE2 regulates muscle stem cells and enhances regeneration, and another group showed that knocking out the enzyme responsible for PGE2 synthesis has harmful effects on muscles, says Blau. Her team has now found that levels of PGE2 are lower in older than younger mice while levels of the prostaglandin-degrading enzyme 15-PGDH are elevated, and that partially blocking its activity can restore their strength and endurance.
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The study is newly published in Science (DOI: 10.1126/science.abc8059). Overexpression of 15-PGDH in young mice induced muscle loss, and its short-term inhibition reversed muscle wasting associated with aging. Notably, inhibiting 15-PGDH restored PGE2 in aged muscles to physiological levels characteristic of young muscles. This restoration of PGE2 to youthful levels led to a pronounced increase in strength in elderly mice.
Blau notes that the 15-PGDH inhibitor had a notably robust effect on muscle strength—a roughly 15% gain in the aged mice after one month of treatment. “Humans after the age of 50 lose 10%-15% of their muscle strength and mass per decade, so if they could get that back with a short-term treatment… it would be really remarkable.”
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A small molecule inhibitor of 15-PGDH was formerly used to promote tissue regeneration in mouse models of colon and liver injury by increasing level of PGE2, Blau says. Since PGE2 stimulates stem cells, the Stanford team reasoned that the same pathway might also be important in aging.
It came as a welcome surprise that elevating PEG2 by inhibiting 15-PGDH led to body-wide improvement in aged mice, she notes. PGE2 has a “very short” half-life, making it difficult to translate into a therapy. “You would have to inject it right into the muscles.”
Read full story:
https://www.bio-itworld.com/news/2021/03/17/stanford-researchers-find-culprit-in-muscle-aging-and-how-to-knock-it-down
More Research Reading:
Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength
Prostaglandin E2 (PGE2), an eicosanoid that mediates inflammatory responses, also supports the function of muscle stem cells. Palla et al. found that loss of PGE2 in aging mice contributes to loss of muscle and appears to be a consequence of increased activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that degrades PGE2 (see the Perspective by Becker and Rudolph). Restoring PGE2 concentrations by inhibiting 15-PGDH in older mice improved muscle function. Decreased activity of 15-PGDH in older animals had beneficial effects that included decreased proteolysis and transforming growth factor–β signaling and increased mitochondrial function and autophagy. The findings reveal a potential therapeutic strategy to help maintain muscle mass and function during aging.
To test if the disseminated muscle wasting seen in sarcopenia could be overcome by systemic delivery of a small-molecule inhibitor of 15-PGDH, we treated aged mice and young control mice daily intraperitoneally with SW033291 (SW) or vehicle (10) (Fig. 2A). SW is an inhibitor with specificity for 15-PGDH in vitro (k i of 0.1 nM) (10). In vivo, SW increases amounts of PGE2 twofold, and increases amounts of PGD2 to a lesser extent in bone marrow, colon, lung, and liver, which augments regeneration following injury of these tissues in young mice (10). After 1 month of daily intraperitoneal SW treatment, 15-PGDH specific activity was significantly reduced in aged muscles and amounts of PGE2 and PGD2 (detected by LC-MS/MS) were increased in young and aged muscles (Fig. 2, B and C, and fig. S7, A and B). Histological analysis revealed that myofiber cross-sectional area was significantly augmented in SW-treated aged mice, indicating muscle hypertrophy (Fig. 2, D to F). Fiber type analysis revealed that SW treatment promoted an increase in the cross-sectional area of both oxidative (type IIa) and glycolytic (type IIb) fast twitch fibers (Fig. 2. G to J). Young mice treated with SW exhibited a trend toward increased muscle mass and absolute strength, which reached statistical significance for plantar flexor force difference compared to baseline
https://www.science.org/doi/10.1126/science.abc8059
Orally Bioavailable Quinoxaline Inhibitors of 15-Prostaglandin Dehydrogenase (15-PGDH) Promote Tissue Repair and Regeneration
15-Prostaglandin dehydrogenase (15-PGDH) regulates the concentration of prostaglandin E2 in vivo . Inhibitors of 15-PGDH elevate PGE2 levels and promote tissue repair and regeneration. Here, we describe a novel class of quinoxaline amides that show potent inhibition of 15-PGDH, good oral bioavailability, and protective activity in mouse models of ulcerative colitis and recovery from bone marrow transplantation.
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c01299
Availability:
Dinoprostone is available inexpensively from Indian sources as a tablet or gel ($15 to $34 US) per package (but it doesn’t seem that just taking the medication, or applying the gel would work)
https://dir.indiamart.com/search.mp?ss=Dinoprostone&prdsrc=1&res=RC2
Chemical / Drug Tested successfully in Blau research (via daily injections in mice)
Background
Helen Blau’s Lab at Stanford
https://med.stanford.edu/blau-lab.html
https://med.stanford.edu/blau-lab/research/rejuvenation-of-aged-muscle-stem-cells-and-tissues.html
