• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
- - - - -

Rapamycin Fails to Improve Cognitive and Aging Outcomes in Pilot Human Trial

rapamycin

  • Please log in to reply
10 replies to this topic
⌛⇒ write a quiz!

#1 Michael

  • Advisor, Moderator
  • 1,200 posts
  • 1,626
  • Location:Location Location

Posted 26 April 2018 - 11:35 PM


All:
 
To my surprise, this seems only to have been mentioned here, and the lede was totally buried ...
 

Exp Gerontol. 2018 May;105:53-69. doi: 10.1016/j.exger.2017.12.026. Epub 2018 Feb 3.
A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.
Kraig E1, Linehan LA2, Liang H3, Romo TQ4, Liu Q5, Wu Y6, Benavides AD7, Curiel TJ8, Javors MA9, Musi N10, Chiodo L11, Koek W12, Gelfond JAL13, Kellogg DL Jr.10

... we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70-95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily. Although three subjects withdrew, 11 RAPA and 14 controls completed at least 8 weeks of treatment and were included in the analysis.
 
We monitored for changes that would indicate detrimental effects of RAPA treatment on metabolism, including both standard clinical laboratory assays (CBC, CMP, HbA1c) and oral glucose tolerance tests (OGTTs).
 
We also monitored parameters typically associated with aging that could potentially be modified by RAPA; these included cognitive function which was assessed by three different tools: Executive Interview-25 (EXIT25); Saint Louis University Mental Status Exam (SLUMS); and Texas Assessment of Processing Speed (TAPS). In addition, physical performance was measured by handgrip strength and 40-foot timed walks. Lastly, changes in general parameters of healthy immune aging, including serum pro-inflammatory cytokine levels and blood cell subsets, were assessed.
 
Five subjects reported potential adverse side effects; in the RAPA group, these were limited to facial rash (1 subject), stomatitis (1 subject) and gastrointestinal issues (2 subjects) whereas placebo treated subjects only reported stomatitis (1 subject). Although no other adverse events were reported, statistically significant decrements in several erythrocyte parameters including hemoglobin (HgB) and hematocrit (Hct) as well as in red blood cell count (RBC), red blood cell distribution width (RDW), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed in the RAPA-treatment group. None of these changes manifested clinically significant effects during the short duration of this study.
 
Similarly, no changes were noted in any other clinical laboratory, cognitive, physical performance, or self-perceived health status measure over the study period. Immune parameters were largely unchanged as well ...
 
Importantly, the OGTTs revealed no RAPA-induced change in blood glucose concentration, insulin secretion, and insulin sensitivity. Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a trial with a larger sample size and longer treatment duration is warranted.

PMID: 29408453

PMCID: PMC5869166

DOI: 10.1016/j.exger.2017.12.026


This was a small study and quite short-term, but it's still pretty disappointing. I'd've at least expected some effects on inflammatory cytokines and subjective health status. The latter is, of course, the kind of parameter most subject to placebo effects.

 

Good to see no effects on OGTT.


  • Ill informed x 1
  • Informative x 1

#2 RWhigham

  • Member
  • 397 posts
  • 348
  • Location:United States
  • NO

Posted 27 April 2018 - 02:07 AM

... we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70-95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily

The above study is not applicable to the recommended use of rapamycin for life extension.The alleged benefit of rapamycin is from intermittent inhibition of TOR-1 while not inhibiting TOR-2 by once weekly doses.. TOR-1 inhibition occurs quickly; TOR-2 inhibition takes longer. TOR-1 is inhibited following each weekly dose, but the 60-hr half clears the dose each week before TOR-2 is significantly inhibited. 


Edited by RWhigham, 27 April 2018 - 02:10 AM.

  • Good Point x 3

sponsored ad

  • Advert
Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

#3 Michael

  • Topic Starter
  • Advisor, Moderator
  • 1,200 posts
  • 1,626
  • Location:Location Location

Posted 27 April 2018 - 03:07 AM

... we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70-95 years); subjects were randomized to receive either [/font][/color]1 mg RAPA or placebo daily.


The above study is not applicable to the recommended use of rapamycin for life extension.

 
As I've pointed out more than once, this isn't true: the vast majority of studies on CR for anti-aging purposes, including all the fully-powered life-extension studies (from the 2009 NIA ITP breakthrough onward) have used daily dosages. There are a three underpowered lifespan studies with intermittent rapa, as well as a number of suggestive shorter-term studies and a human influenza vaccination study with everolimus.
 

The alleged benefit of rapamycin is from intermittent inhibition of TOR-1 while not inhibiting TOR-2 by once weekly doses.


That's the rationale for investigating rapalogs and regimens (like intermittent dosing) in order to minimize possible side-effects (especially insulin resistance in males), but it's not fundamental to the anti-aging effect: again, daily rapa robustly works, whereas no one has yet done a fully-powered lifespan study with intermittent dosing in WT mammals (let alone one in both genders).
 
Note, in any case, that rapa itself is already mTORC1-biased — and that the main reason to try to minimize mTORC2 inhibition (glucose intolerance) did not emerge in this trial of daily rapa.


  • Ill informed x 1
  • Good Point x 1
  • Informative x 1

#4 Razor444

  • Guest
  • 237 posts
  • 65
  • Location:UK

Posted 27 April 2018 - 09:33 AM

The study referenced here is for 8 weeks. I was listening to a recent Joe Rogan pod w/ Peter Attia, and Peter waxed about a 12-week study in dogs which showed improved biomarkers. So even though 8 weeks is short, it's not out of the realm of possibility that the metrics may have improved.

 

I take a bunch of medications to help w/ an autoimmune disorder -- including low dose statins, and an ACE inhibitor. I think one of them reduces the effectiveness of RAPA. I say that because I take 2mg every other day at the moment and don't get mouth sores. Previously, I took 1mg every other day and did.

 

Given the age of the cohort (70-95), they could well be on a bunch of meds which affect the metabolism of RAPA. I mean, how does an immune suppressant *not* reduce pro-inflammatory cytokines?

 

 



#5 Andey

  • Guest
  • 501 posts
  • 131
  • Location:Kiev, Ukraine

Posted 27 April 2018 - 10:53 AM

I don't believe it shows anything than study authors wrote "it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy"

There is simply not enough data to support the claim that "Rapamycin Fails to Improve Cognitive and Aging Outcomes". 

 

It also may be a false promise overall, to improve cognitive and aging outcomes means RAPA should effectively make somebody younger, to repair aging damage etc. What is the supposed MOA for this?


Edited by Andey, 27 April 2018 - 11:00 AM.

  • Well Written x 1

#6 RWhigham

  • Member
  • 397 posts
  • 348
  • Location:United States
  • NO

Posted 27 April 2018 - 08:57 PM

I don't believe it shows anything than study authors wrote "it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy"

There is simply not enough data to support the claim that "Rapamycin Fails to Improve Cognitive and Aging Outcomes". 

 

It also may be a false promise overall, to improve cognitive and aging outcomes means RAPA should effectively make somebody younger, to repair aging damage etc. What is the supposed MOA for this?

 

Blagosklonny promotes rapamycin to slow aging, not reverse it. For rejuvenation we need a protocol verified by DNA methylation tests See

 

Horvath Clock tracks rejuvenation:

Cells in a culture treated with the Yamanaka iPSC (induced pluripotent stem cells) factors OSKM took 20 days to regress to embryonic stem cells. During the regression which started at day 3 to 7 the Horvath Clock of the cells reversed at a rate of about 3.8 yr per day. i.e. there is a progressive biological rejuvenation tracked by the Horvath clock

 

Reference:

Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity  "To understand the dynamics of eAge within a reprogramming time-course, we calculated eAge using Horvath’s multi-tissue age predictor over a previously published 49-day reprogramming time-course on HDFs (Ohnuki et al. 2014; Horvath 2013). Epigenetic rejuvenation, i.e. decrease of eAge, commenced between days 3 and 7 after OSKM transduction and continued until day 20, when it was stably reset to zero (Fig. 1a). A broken stick model with two linear sections starting from day 3 showed a good fit to the observed data and measured a steady decrease with 3.8 years per day until day 20"


Edited by RWhigham, 27 April 2018 - 09:13 PM.

  • Informative x 2
  • Good Point x 1

#7 Michael

  • Topic Starter
  • Advisor, Moderator
  • 1,200 posts
  • 1,626
  • Location:Location Location

Posted 30 April 2018 - 03:36 AM

I take a bunch of medications to help w/ an autoimmune disorder -- including low dose statins, and an ACE inhibitor. I think one of them reduces the effectiveness of RAPA. I say that because I take 2mg every other day at the moment and don't get mouth sores. Previously, I took 1mg every other day and did.
 
Given the age of the cohort (70-95), they could well be on a bunch of meds which affect the metabolism of RAPA.


That's not a crazy thought, but they selected for "generally healthy older adults (aged 70-95 years)” (of course, this is with the usual Orwellian subtext of “healthy for a 70-95 y.o.,” but still), and they excluded subjects with “evidence of diabetes (A1c ≥6.5), being treated with a medication that would affect glucose homeostasis, history of skin ulcers or poor wound healing, smoking, warfarin anticoagulation treatment, on a drug known to affect cytochrome P450 3A due to its role in RAPA metabolism, or treatment with an immunosuppressant agent (including glucocorticoids) within the last year, liver disease, recent history (within 6 months) of myocardial infarction, active coronary disease, or intestinal disorders.” So that should go quite a long ways to rule out those kinds of confounders.
 

I mean, how does an immune suppressant *not* reduce pro-inflammatory cytokines?

 
Aging people's inflammation may be driven by different immune processes than those that RAPA inhibits. Rapa was long thought to be largely a matter of T-cell suppression, but it's all turned out to be very complex. Similarly, how does an immune suppressant *not* reduce response to influenza vaccine? And yet ...
 

I don't believe it shows anything than study authors wrote "it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy"
There is simply not enough data to support the claim that "Rapamycin Fails to Improve Cognitive and Aging Outcomes".


Read the whole subject line ;) . "Rapamycin Fails to Improve Cognitive and Aging Outcomes in Pilot Human Trial" — which is just what they report: "We also monitored parameters typically associated with aging that could potentially be modified by RAPA; these included cognitive function ... physical performance ... general parameters of healthy immune aging ... No changes were noted in any other clinical laboratory, cognitive, physical performance, or self-perceived health status measure over the study period. Immune parameters were largely unchanged as well."

 

It also may be a false promise overall, to improve cognitive and aging outcomes means RAPA should effectively make somebody younger, to repair aging damage etc. What is the supposed MOA for this?


No one claims it actually repairs damage; however, there are certainly many studies in which rapa has improved aging outcomes in quite short-term studies, including some in which aging-relevant parameters have been improved over baseline and not just had their progression slowed.

 


  • like x 2
  • Ill informed x 1
  • Agree x 1

#8 QuestforLife

  • Member
  • 327 posts
  • 157
  • Location:UK

Posted 30 April 2018 - 09:20 AM

The intermittent (weekly) users that I am in correspondance with report a gradual but eventually substantial improvement in health when on rapamycin. This is in marked contrast to many supplements or medications taken by members of this site, where users get all enthusiastic only for the effects, real or imagined, to fade.

 

The most interesting reports from rapamycin users are of improved athletic performance. It may well be that reducing mTOR intermittently adjusts the balance of mitobiogenesis and mitophagy in favour of a healthier 'herd' of mitochondria.

 

These anecdotal reports are not a formal study, but there must be 10s of people on intermittent rapamycin for a year or two now, and they all seem to report positive health outcomes.



#9 Razor444

  • Guest
  • 237 posts
  • 65
  • Location:UK

Posted 30 April 2018 - 09:49 AM

on a drug known to affect cytochrome P450 3A due to its role in RAPA metabolism, or treatment with an immunosuppressant agent (including glucocorticoids) within the last year, liver disease, recent history (within 6 months) of myocardial infarction, active coronary disease, or intestinal disorders.” So that should go quite a long ways to rule out those kinds of confounders.
 

 
Aging people's inflammation may be driven by different immune processes than those that RAPA inhibits. Rapa was long thought to be largely a matter of T-cell suppression, but it's all turned out to be very complex. Similarly, how does an immune suppressant *not* reduce response to influenza vaccine? And yet ...
 

 

I hadn't realised they'd taken measures re. CYP3A4 enzyme. That does make sense. It seems like something which would affect the experiment to a large degree.

 

Good point on the flu vaccine.



#10 brianmdelaney

  • Guest
  • 14 posts
  • 6
  • Location:Stockholm or South Florida or Bogotá

Posted 28 July 2018 - 05:58 PM

These anecdotal reports are not a formal study, but there must be 10s of people on intermittent rapamycin for a year or two now, and they all seem to report positive health outcomes.

 

Are these people typically taking 5 or so mg / week?



sponsored ad

  • Advert
Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

#11 QuestforLife

  • Member
  • 327 posts
  • 157
  • Location:UK

Posted 21 August 2018 - 01:45 PM

Are these people typically taking 5 or so mg / week?

 

Varies from 2-6mg/week, mainly depending on age, with older people trialing higher doses.

 

I am currently trialling once a month rather than once a week to compare the effects.







Also tagged with one or more of these keywords: rapamycin

1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users