I remember (I think) reading here, before I became a ‘user’, that age-health related gains made by taking Rapa… stayed with you if you ever stopped taking it. So if I regressed my body-age through Rapa by 5 years…it would take about 5 years for that benefit to wear off…or I would start aging normally from that age regressed age.
Is this memory a good one?
What is the latest information on this ?
This is perhaps one of the key mechanistic questions. I take the view that additional autophagy (mitophagy) that improves mitochondrial efficiency is a discrete process that is enhanced with rapamycin. Hence each cycle of efficiency improvements lasts until the normal gradual deterioration of efficiency that occurs with metabolism has erased it.
There is evidence of interventions at an earlier stage having effects at later points.
However, some people disagree as to what the mechanism is.
The “carryover affect” theory was what encouraged me to take it in the first place. Inspired by: Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice | eLife
Summary;
The Method: Researchers took middle-aged mice (20 months old, roughly equivalent to a 60-to-65-year-old human) and gave them rapamycin for just 3 months (90 days). Treatment was then permanently stopped, and the mice were followed for the rest of their lives.
The Results: Despite stopping the drug, the treated mice experienced a 60% increase in remaining life expectancy compared to the control group.
Healthspan Improvements: Long after stopping the drug, the mice showed sustained improvements in muscle strength, motor coordination, and a remodeled gut microbiome.
The reasoning is debated but could be…
Autophagy Reset: Rapamycin triggers a massive cellular cleanup process (autophagy). Clearing out decades of cellular “garbage” (damaged proteins and organelles) lowers systemic inflammation long after the drug leaves the system.
Microbiome Remodeling: The 3-month trial showed a persistent shift toward a younger, healthier gut microbiome (specifically an increase in segmented filamentous bacteria), which provides long-lasting metabolic and immune support.
Stem Cell Rejuvenation: Transient mTOR inhibition helps reset exhausted adult stem cell niches, allowing tissues to maintain better regenerative capacity even after normal aging rates resume.
This is perhaps the core debate we should have on this forum. To what extent is it better to have a deeper “spring clean” (whatever the mechanism is) less frequently or a shallower spring clean more frequently.
I think I have made my view clear on this.
So the mice were an homogenous group being all 20 months old. the treatment group lived approximately 1.2 months longer. I do not see a statistical justification to express it as a percentage
unless several age groups are compared.
Mechanistically I could imagine a cleanup whereafter formation of new garbage takes place at the old rate.
can you please give me your thoughts on what that means for rapa use at advanced age.
I’ve always viewed it as just slowing the rate of aging only while you take it by down tuning your “growthiness”. I’m open to be being convinced otherwise though.
Metaphors will have to suffice until we can replace them with a more complete understanding. Based on the processes for which our understanding is more advanced, most seem continuous regulatory processes via feedback loops. Are there any that are loge interval periodic/cyclical? There probably are but I cannot think of one. Of course, the line between continuous and cyclical is a calculus.
The daily circadian cycle is probably part of the anabolic catabolic cycle
I’d love some more thoughts/debate on this. I’ve taken high doses in the past for the bbb penetration “hope”. But i wonder of we should instead think of a plan B…
Thought 1. Everolimus is better than Rapamycin for the brain spring clean because Everolimus isn’t transported out as easily as rapa (via efflux transporter P-gp) so we dont have to worry about high dosing.
Rapa: “One reasonably well-controlled rodent study (Crestani et al., and separately the Harrison ITP group tissue distribution work) puts brain:plasma at approximately 0.10–0.15 at low doses, rising to 0.25–0.35 at higher doses — consistent with partial P-gp saturation at the efflux transporter.”
Everolimus. Several papers in the TSC preclinical literature (Eklund et al., Sunnen et al.) reporting ratios in the 0.25–0.40 range at therapeutic doses. This is generally higher than rapamycin in the same study conditions — somewhat counterintuitive given lower lipophilicity, but potentially explained by differences in P-gp affinity
Thought 2. Give BBB penetration a boost with : a. Sauna/hot bath
Logic: Elevating core body temperature to a state of mild hyperthermia 38.5C accelerates cerebral blood flow and physically destabilizes the strict architecture of the BBB. Heat stress temporarily alters tight junction phosphorylation and downregulates P-gp pump transcription, creating a brief window for highly lipophilic molecules like rapamycin to diffuse through. timed to coincide with peak rapamycin serum levels (roughly 1–2 hours post-ingestion). fwiw Claude guesstimates a 5 -25% boost to brain rapamycin from this.
b. Evening dosing
Logic: The expression and mechanical pumping efficiency of P-gp efflux transporters at the BBB are dictated by autonomous circadian clock genes (like Bmal1 and Per2). In humans, P-gp expression naturally cycles and hits its lowest operational trough during the early hours of the nocturnal sleep cycle, making the barrier naturally more permeable. fwiw Claude guesstimates a 15 -25% boost to brain rapamycin from this
Thought 3. Adding other brain autophagy interventions on dosing day
Spermidine ? TRE? Urolothin A for mitophagy?