The Mitochondrial Master Switch: Rethinking Cellular Energy as the Locus of Chronic Disease

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#21

That is a problem. It’s demonstrated that SS 31 helps the damaged mito’s function better. It also contributes to mito biogenesis, hopefully the new mito’s being generated are better than the repaired ones.

Theoretically this could enable better health while new mito’s come online?? The longer term benefit would depend on the quality of the new ones. It appears that mito’s turn over fairly quickly and a 1 month course of SS 31 might setup the production of healthier ones than without SS 31 as we age. Again the “problem” of ongoing production without SS 31 remains an issue.

Evidence suggests that during SS‑31 treatment, newly generated or remodeled mitochondria tend to function more normally and with higher “quality” than the previously damaged pool, but this reflects both repair of existing mitochondria and improved turnover rather than a simple swap to entirely new organelles.

One aspect of SS 31 is that there was no discernable benefit in younger people, who would have fewer damaged mito’s, this tells us that as a repair agent, it is selective, it doesn’t “boost” healthy mito’s.

SS 31 peptide - with longer term treatment, does t (1).pdf (420.8 KB)

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#22

If one were to take MOTSc and SS31 for kidney rejuvenation, what should be the order of injection. Which comes first. I believe MOTSc should be administered in the mornings. Any advice? Cheers

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#23

This is something I had not looked into, so…

Prompt:

What is the degradation rate for any mitochondrial health benefits of SS-31, once dosing is stopped? What does the best clinical and scientific evidence suggest is the “staying power” of any benefits gained from SS-31 use?

Gemini Pro response:

Based on the pharmacokinetics and clinical data from both human trials (MMPOWER) and longevity-focused animal models, here is the analysis of the “staying power” of SS-31 (Elamipretide).

Executive Summary: The “Legacy Effect”

Bottom Line: While the peptide itself clears your system in hours, the structural benefits to the mitochondria likely degrade over a period of 4 to 12 weeks after cessation.

The evidence suggests a “Remission” model rather than a “Cure” or “Dependency” model. By stabilizing cardiolipin and stopping the oxidative “rusting” of the machinery, SS-31 allows the mitochondria to physically rebuild their internal structure (cristae). Once you stop, it takes time for the natural aging process to tear that structure down again.

1. Pharmacokinetics vs. Pharmacodynamics

It is crucial to distinguish between the drug’s presence and its biological effect.

  • The Drug (Pharmacokinetics): SS-31 has a very short half-life.

  • Plasma Half-Life: ~2 hours.

  • Tissue Retention: ~4 hours.

  • Implication: If you skip a dose, the active “shield” is gone immediately. There is no reservoir of the drug building up in your tissues.

  • The Effect (Pharmacodynamics): The biological benefit persists because SS-31 is a structural repair agent, not just a fuel.

  • Mechanism: SS-31 breaks the “Vicious Cycle” of ROS (Reactive Oxygen Species). By stopping the leak of free radicals, you allow the cell’s natural repair enzymes to fix the cristae.

  • Washout: When you stop the drug, the ROS leak returns immediately. However, it takes time for that accumulating rust to degrade the clean, repaired machinery back to its previous dysfunction.

2. Evidence of Durability (“Stay Power”)

The Best Case: 3+ Months (Aging Model)

In a study on age-related visual decline (a proxy for neural/sensory aging), mice treated with SS-31 daily for 2 months showed reversed visual decline.

  • The Result: Remarkably, the recovered function persisted for at least 3 months after treatment was withdrawn.
  • Why? Neural tissue has low turnover. Once the mitochondria were repaired, the oxidative stress accumulation was slow enough that the benefits lasted a significant portion of the animal’s remaining lifespan.

The Realistic Human Case: <4 Weeks (Myopathy Model)

In the MMPOWER-2 human clinical trial (Primary Mitochondrial Myopathy), researchers used a crossover design with a 4-week washout period between treatment and placebo phases.

  • The Result: Subjects who took SS-31 first and then switched to placebo did see a decline in their performance (6-Minute Walk Test) during the washout, but they often did not crash all the way back to baseline immediately.
  • Implication: In active muscle tissue with high energetic demands, the degradation happens faster than in the eye. The “slide” back to baseline likely takes 4–6 weeks.

3. Rate of Degradation: The “Slide” Trajectory

Based on the “Double Hit” data and washout studies, the degradation trajectory likely looks like this:

Time Post-Cessation Physiological Status Practical Feeling
Hours 0–24 Peptide clears. Cardiolipin is no longer actively stabilized. No change (structural momentum).
Week 1 ROS leak resumes (“rusting” begins). “Afterglow” effect; performance remains high.
Weeks 2–4 Cumulative oxidative damage begins to distort cristae structure again. Noticeable loss of “top-end” endurance or recovery speed.
Weeks 5–8 Mitochondrial Efficiency (P/O Ratio) returns to pre-treatment baseline. Full “washout.” Benefits are effectively lost.

4. Strategic Implication: Can You “Pulse” It?

Given that the repair takes weeks to establish and weeks to degrade, cycling is a viable strategy to manage the high cost of the peptide while maintaining majority benefits.

  • The “Maintenance” Cycle: A protocol of 8 weeks ON / 4 weeks OFF might theoretically maintain ~80% of the peak benefit.
  • ON Phase: You actively repair cristae and maximize ATP.
  • OFF Phase: You ride the “legacy effect” as it slowly degrades, restarting the next cycle before you hit baseline.

Note - Here is another response with links to papers supporting claims:

SS31DegradationCurve.pdf (121.2 KB)

Next Step

Since the “Quantity” deficit (Volume Density) requires a different stimulus that might be more durable (biogenesis), would you like me to construct a “Hybrid Pulsing Protocol”? This would alternate SS-31 cycles (Quality) with high-intensity Zone 2/Urolithin A cycles (Quantity) to keep both metrics elevated without requiring year-round daily peptide injection.

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#24

Here is the Hybrid Pulsing Protocol, designed to alternate between stabilizing mitochondrial structure (Quality) and forcing biogenesis/clearance (Quantity).

This protocol relies on a “Fix, then Purge” logic. SS-31 stabilizes cristae, potentially reducing the depolarization signals that trigger mitophagy. Therefore, the “OFF” phase is not passive recovery; it is an active “Purge & Build” phase where you aggressively clear the mitochondria that fail once the peptide support is removed.

The 8:4 “Mitochondrial Pulse” Cycle

Cycle Structure: 8 Weeks ON / 4 Weeks OFF

Annual Frequency: 4.3 Cycles per year.

Phase 1: Structural Restoration (Weeks 1–8)

Objective: Restore the P/O Ratio (Efficiency). Fix the “Quality” defect.

Mechanism: SS-31 stabilizes cardiolipin, optimizing electron transfer and minimizing ROS leak.

  • Peptide Protocol:
    • Compound: SS-31 (Elamipretide).
    • Dosage: 40mg Subcutaneous (SC) injection, once daily.
    • Timing: Morning, irrespective of food.
    • Note: During this phase, mitophagy signals may naturally decrease because the peptide is artificially propping up membrane potential (limiting the “eat me” signal).
  • Supportive Stack:
    • Urolithin A: Maintenance Dose (250mg–500mg). Keep a baseline presence, but do not aggressively drive clearance while investing in repair.
    • Exercise: Zone 2 “Maintenance” Volume. 3x weekly, 45 mins. Focus on maintaining baseline flux, not forcing adaptation.
  • Evidence Basis:

Phase 2: Purge & Build (Weeks 9–12)

Objective: Exploit the “Washout.” Restore the Volume Density (Quantity).

Mechanism: As SS-31 clears (Hours 0–24), the weakest mitochondria will begin to depolarize. You must immediately induce Mitophagy to clear this debris and trigger Biogenesis (PGC-1α) to replace them with fresh organelles.

Why This Timing Works (The Pharmacodynamic Rationale)

1. The “Soft Landing” (Weeks 9–10):

The “legacy effect” of SS-31 means your cristae structure is still relatively intact for roughly 2 weeks post-cessation. This allows you to perform High-Volume Zone 2 training with greater efficiency than your baseline, allowing for a higher training load (and thus a stronger biogenic signal) than you could achieve otherwise.

2. The “Hard Reset” (Weeks 11–12):

By week 3-4 of the OFF phase, the structural benefits have largely degraded. Oxidative stress rises. This is the critical window where High-Dose Urolithin A prevents the accumulation of senescent “zombie” mitochondria.

3. Restarting (Week 13):

You re-introduce SS-31 before the tissue regresses to a pathological state. You are effectively “ratcheting” the system:

  • Cycle 1: Repair old mitochondria $\to$ Build new ones.
  • Cycle 2: Repair the new mitochondria (which are now aging) $\to$ Build more.

Critical Implementation Note: NAD+ Precursors

If you utilize NAD+ precursors (NMN/NR), they should be prioritized during Phase 2 (The OFF Phase).

Next Step

Would you like me to construct a Lactate Threshold Testing Protocol (using a portable meter) so you can accurately calibrate the Zone 2 intensity required for Phase 2? Accurate intensity is the primary failure point in biogenesis protocols.

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#25

The problem (forgetting the expense) is the short half-life of SS-31. We need something that does the same thing with a longer half-life. I hope someone is working on this.

The elimination half-life of subcutaneously (SC) injected SS-31 (elamipretide) in the human body is approximately 2 hours.

Key pharmacokinetic details for SC administration in humans include:

  • Absorption: Peak plasma concentrations are typically reached within 0.5 to 1 hour after injection.
  • Bioavailability: The absolute bioavailability of a subcutaneous dose is high, at approximately 92%.
  • Distribution: It is distributed throughout total body water with a volume of distribution of roughly 0.5 L/kg and approximately 39% protein binding.
  • Metabolism & Elimination: It undergoes sequential C-terminal degradation into inactive metabolites (M1 and M2). Roughly 100% of the dose and its metabolites are recovered in the urine within 48 hours in individuals with normal renal function.
  • Accumulation: There is minimal accumulation of the parent drug with standard once-daily dosing.

Here is some prescription dosing information. Ref

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#26

That is an issue, but it still works for Barth’s syndrome. So half-life is not an impediment for that condition.

This is also why I split my high dose 20mg per day into 2 injections of 10mg, morning and night. with a 5 day cycle. Total 100mg used

I’m currently into about day 20 of a 30 day low dose (3.33mg per day) routine.

Keep in mind this compound “fixes” a particular problem in mito’s that themselves have 5 to 11 day life. With this kind of turnover, repairing the damaged mito’s and getting rid of the damaged mito’s, then replacing the old with new mito’s ones is still “probably” a benefit,

I see this as a 2 or 3 step process.

  1. repair existing damaged mito’s with a high dose cycle
  2. support mitophagy and production of healthy new ones
  3. do this in cycles for “normal” people that are aging.

I don’t think it would be necessary to do this as a daily intervention to get some benefit.

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#27

Because they work very differently, I don’t know that it matters. But I’d probably start with the SS 31.

If I had any indication of CKD I’d be taking a GLP1-ra. - see page 6 of this PDF.

GLP1-RA - how do they work, explain the science, u.pdf (846.2 KB)

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#28

I had never heard of that particular syndrome because:

Barth syndrome (BTHS) is an ultra-rare, life-threatening genetic disorder that primarily affects males. It is a multisystem metabolic condition characterized by heart problems, muscle weakness, and a weakened immune system.
Ref1

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#29

This is the mitochondrial condition that SS 31 is FDA approved to treat and where all the good data comes from.

Barth syndrome is a genetic mitochondrial disorder in which defective remodeling of the phospholipid cardiolipin disrupts many aspects of mitochondrial structure and function, especially in heart and skeletal muscle cells

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#30

Hard to say much on this in one post… Being a member of Alex Kikels TPC-Army skool, $200/mo, Anthony Castor’s Skool (free and super excellent coach), and Chris Duffin’s Skool, free and decent, and off course Hunter/Campbell on youtube;

There is not one dose fits all for any of the peptides especially the mitochondrial family; MOTSC, SS-31. Small molecules SLU-pp-332, 5AminoMq and probably more. There is a point where the mito can be over stimulated and you experience a caffeine like brain fog / and over stimulation. So more is not better especially when adding in SLU and maybe BAM15 which are amplifiers.

I’ve learned that the personal dosing, protocol, is layered, cycled, and slowly built up. Finances can be the limiitor. Unless you buy from places like nexaph.com or even closer to China, then SS-31 in the mgs’s /day are possible, but with likely over doing it.

Folks can say peptides dont work. And that may be true for them at the doses and at their metabolic health/dis-health/BMI/SAD diet inputs… Lots of bodies are not ready for peptides its a waste. Fix metabolic health first starting with HRT!!! and Lifting some weights and fixing the diet. THEN GLP-1s, in a few months and pounds lost then the mitochondria stacks. I’ll add though its ok to start Urilithin-a any time and possibly continuously. But Kikel will cycle even Urolithin-a… Using epigenetic nudging, hormesis, to stair step health and function up.

Just tersely summarizing a complicated topic of dosing, layering, cycling peptides.

At least join the 2 free Skool groups I know of. Probably a few others that are useful re peptides, health, muscle growth. Kikel’s TPC is not a general tutorial type group. Anthony Castore’s group covers a wide range of topics rifle shots at a time.

A bit of a sales pitch-y peptide/bioregulator education site: https://peptidescienceinstitute.com, I just received their Peptide Master book. An encyclopedia. TBD the value. But its; education for education’s sake at the least. The gap all along is: case studies, dosing protocols combining many inputs to effect a health improvement. Too much talk about just one peptide, one thing.

Best to all, curt

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#31

How do you promote only healthy mitochondria to be replenish? My understanding is that you need some kind of stressor to eliminate the weak ones.

#32

The myopothy model strikes me as an extreme case, a degree of illness that many of us are not contending with yet. The dosing protocol may be different, and much less expensive, for the more generic problems of aging.

That’s what I am trying to do. In one of his videos, Alex Kikel recommends SS-31 specifically for the kidneys. As does Hazel Szeto. I think SS-31in combination with retatrutide would have the most benefit.

40 mg/day, but that’s for Barth syndrome, also an extreme case.

I took a quick look at his group. In my opinion, this is still the best site on the web.

Me either.

There is a wide price range on Amazon, from $25 to $125. Does anyone have a recommendation?

Researchers have also shown that Urolithin B is as biologically active as its sibling. In particular, it reduces fibrosis and improves renal function in rats.

https://www.sciencedirect.com/science/article/pii/S1756464619306723

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#33

Could you do an oral glucose tolerance test? 75g pure glucose at once fasted while wearing a CGM.
That would be a good standard data point.

I did that some time ago to compare glucose handling with and without rapamycin: Hyperglycemia caused by rapamycin

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#34

Since new mito’s are created by the division of existing mito’s, i.e. fusion, then “quality control” through mitophagy is important. As dysfunctional mito will generate more dysfunctional mito’s.

Theoretically if one were to use SS 31 to repair one aspect of a damaged mito, when it comes time to divide and produce new ones. that repaired mito may produce healthier mito’s.?

With respect to MOTS-c

In cell and animal studies, MOTS‑c increases expression of mitophagy‑associated genes such as PINK1, PARK2 (Parkin), and ATG7, alongside genes for mitochondrial biogenesis and fusion, suggesting coordinated activation of mitochondrial turnover

mitophagy and aging (1).pdf (687.9 KB)

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#35

Re Urolithin A I wish I could find the testing report on actual content. Like NMN et al, there’s a wide actual content issue. BUT one can hopefully side step that by going with higher quality vendors: https://www.hansensupplements.com

donotage.com (??). Of course Time Line… ;(

best of luck, curt

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#36

Also in Kikels group, TPC-army, is “The kidney Doc” Fiona Chin. Google for Fiona’s youtube channel, videos. She LOVES klotho for kidney rejuvination. Us TPC members have access to buying a private source of 1-Klotho, a daily dose. A publicly available of a-klotho, dosed every 2 weeks from Biolongevitylabs.com. Fiona is taking the TPC version 300mcg every other day.

Fiona has detailed kidney protocols in her videos, her website (google) and may do consults from here home in Australia.

FWIW, curt

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#37

I bought a few of the timeline gummies 50% off (still expensive though, but they are YUMMY)
I also bought Codeage during the big holiday sales.

When I run out, I’ll switch to Neurogan which are priced the best.

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@curt504
“ Could you do an oral glucose tolerance test? 75g pure glucose at once fasted while wearing a CGM.
That would be a good standard data point.”
I’ve never done anything similar to that. I’ve been wearing CGMs on and off for years, and this was the very first time I only went over 140 1 time, which was yesterday. Normally it’s once per day, even on medication.

Today, I’ll put a new CGM on, so I’ll know in couple of days if my CGM from the last two weeks was a fluke.

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#38

I have UA, 98% = $1.50 per gm bulk powder

#39

@Steve_Combi

UA at 98% at $1.50/gr.
Where?

=== SS-31 dosing, MOTSC dosing.

Maybe this Chris Duffin Skool URL will force bringing up a join link then good, its free. This video in Chris’s post is good, worth watching. Jump over the first 20min of small talk.

The Video off the skool post seems to be a public youtube URL: https://www.youtube.com/watch?v=fVJTRUFRpKo

The SS-31 / MOTSC dosing after 1:15hr

8 week cycle of SS-31 at 5mg/day, then MOTSC for 8 weeks at 5mg/day. +/-

This is alot more then I’ve been doing. So I’ll up dosing. At upon waking I do HGH secretagoge: Ipa/CJC/Tesa + SS-31. 300mcg Ipa and CJC/Tesa sits on top at what ever my mix includes. There’s a risk of wasting some secretagoges since the body can’t put out any more then the nudge of Ipa/CJC/Tesa can push. More is wasted. . I’ll up the SS-31 to 3mg ish from 1mg. One should ramp up slowly noticing side effects.

Best to all, curt

curt

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#40

neurogan urolithin A

Great, the red bottle. Thats the one I buy off Amazon for $99/120 caps at 1000mg.

tnx for the chart!!!

No systemic CGM glucose tolarance test. An idea though. Good luck with your CGM use. I just take an SGLT-2, dapa, ALA, dihtydro berberine. I can’t take metformin, makes me feel litharigic. I’m told by the body builders I needd to take 1g AM + PM to get over the hump. Then there’s the issue of metformin being toxic to mitochondria, so I don’t do metformin…

curt

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