Thread by @mkaeberlein

Really interesting pre-print on effects of middle-age parabiosis in mice. Definitely worth a read.

biorxiv.org/content/10.110…

I like the design here, as it parallels what we did with rapamycin in 2016. Treat from 20-23 months of age and see what happens

/1

I recommend everyone directly compare the two studies

elifesciences.org/articles/16351

We didn’t do multi-omics in our 2016 rapamycin study, but we did do some function measures and disease pathology not included here. Both studies reported lifespan extension

/2

The omics data here are compelling that there is a strong rejuvenation effect from parabiosis that persists for some period of time after the treatment ends. The actual impact on lifespan is significant but appears to be much less than 126 ppm rapamycin

/3

Actual numbers for female B6 median lifespan in the two studies (apples to apples):

Parabiosis controls: ~833 days
Parabiosis treatment: ~875 days
Rapamycin controls: 879 days
Rapamycin treatment: 960 days

Males at the same dose of rapamycin: median lifespan of 1037 days

/4

For additional reference, the effects of parabiosis in absolute numbers (median LS) here are on par with that of nicotinamide riboside and metformin in B6. Both of those were not subsequently validated by the ITP in UMHET3

/5

Also note the rapamycin control mice (no rapamycin) in the 2016 study lived as long as the long-lived parabiosis treated mice in this study. This is unfortunately common in the aging literature and inflates actual magnitude of effect for many interventions

/6

My takehome is that 3 months of parabiosis impressively rejuvenated the -omics signature and extended LS, but probably not as effective as rapamycin under similar conditions. Can’t say for sure, as we would need to test both interventions under the exact same conditions
/7

Not much evidence for healthspan extension here, but if you take the whole literature, you can make that argument. Caveat that healthspan is a qualitative term, not quantitative, so we should all be careful about claiming increased healthspan

ncbi.nlm.nih.gov/labs/pmc/artic…

/8

Could the parabiosis effect be optimized to be bigger than rapamycin? Definitely possible, especially if the “active ingredients” can be isolated. But, as I keep harping on, at some point it would be really nice to have something better than rapamycin that's not 50% CR

/9

The one thing I really wish they’d done: a direct comparison with a parallel 126 ppm rapamycin arm. IMO that would have greatly elevated the impact of this study. Then we’d know relative efficacy of interventions and also how well the -omics clocks actually predict outcomes /10

As I’ve said before, I don’t care what the clocks tell me, if the intervention is weak or ineffective at actually enhancing health and longevity. A big “rejuvenation” in -omics without a comparable extension of health- and/or lifespan just doesn’t excite me 11/11