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

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#8

And since MOTS-C was not mentioned in the initial query, here is the response for a MOTS-C focused prompt:

First the Infographic.

Motsc1
Motsc11920×1136 102 KB

MOTSC2
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MOTSC3
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MOTSC4
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The report:

The Mitochondrial Mitokine Revolution: A Comprehensive Analysis of MOTS-c and SS-31 for the Restoration of Bioenergetic Homeostasis and Longevity

The paradigm of mitochondrial biology has shifted from viewing these organelles as mere passive energy producers to recognizing them as active signaling hubs that dictate cellular and systemic health through a process known as mitohormesis. This report examines the burgeoning field of mitochondrial-derived peptides, specifically focusing on MOTS-c and its potential synergy with the structural stabilizer SS-31 (elamipretide). As age-related decline in mitochondrial function remains a central driver of the aging phenotype—contributing to sarcopenia, metabolic dysfunction, and neurodegeneration—the identification of pharmacological agents that can stimulate biogenesis and restore membrane integrity is of paramount importance to the longevity community.

Full report:

MOTS-c Peptide Longevity Research Analysis.pdf (210.1 KB)

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#9

My first course of SS-31 has improved my kidney function. I am still monitoring my eGFR (creatinine) and it seems to be stable at ~90. I am quite pleased with that. I ran out of SS-31. Waiting for order fulfillment.
I got myself a creatinine meter from AliExpress. I checked against lab readings and is reasonably close and ok for my purposes. Trying to figure out the optimum peptide protocol for my body. Fixing the deficiencies. Cheers

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#10

By how much, measured how? It would be interesting to monitor and track all the key blood and functional markers over time, as you layer on new interventions. Keep reporting back!

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#11

Serum creatinine 06/25 - 1.17, 12/25 - 0.94, 01/26 - 0.99. Am currently on MOTSc. will test in 2 weeks.
Cheers

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#12

Unless I missed it, I don’t see a recommended dose for ss-31. Can you ask, pretty please.

As mentioned in the ss-31 thread:
I’m taking 4.5mg daily. I’ll know for sure in a couple of days when I rule out a bum CGM when I switch it in two days, but I think it’s fixed my glucose spike issue. SORCERY! I have not had one spike over 140 in 12 days. I’m taking less acarbose, too. It doesn’t seem possible

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#13

I can ask… but the question will have to be based on theoretical extrapolations from mice and/or sick people, because I know there is very little data (i.e. probably zero) from good studies on the topic of SS-31 and age-related mitochondrial dysfunction in otherwise healthy humans…

I suspect the best info we have right now is simply what Hazel has told us… nobody knows this peptide and its potential better than her:

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#14

Thank you and that makes sense!

It was her using 5mg daily sublingually that guided my random 4.5 sub q (thinking use a little less to save money because sub q would be a little more bioavailable).

#15

SS31 - I started at 4 mgs and soon titrated up to 10 mgs. Daily dosing. My next round is going to be 20 per day. I have a large lot on order. I did not see any effect on my blood glucose readings. I am diabetic and have a separate armamentarium to deal with it. That is the driver for my focus on kidney health. An effect I see post this peptide is my breathing has become much easier (restriction free). I can take very deep breaths and can expand my lungs considerably. I am going to get VO2 max evaluation in late March to see if there is any real change or is just my imagination!

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#16

Subjectively, I have felt nothing from most of the peptides that I have taken. The exceptions were semax and tirzepatide. I wouldn’t expect younger people to have any subjective benefits from SS-31 (also known as Elamipretide).

With many peptides it is not easy to obtain measurable results from common lab tests.

My searches only found that older people felt subjective benefits. Since I am always looking for ways to combat age-related decline in function, I am going to give it a try soon.

“A standard dose of SS-31 is 5mg, but it may vary depending on factors such as age, weight, and health history. You can expect to take just two doses per week, much fewer than the daily or near-daily administrations common with other peptides.”

"Energy and Fatigue: Users on platforms like Reddit and Facebook report “life-changing” results regarding extreme fatigue, particularly when related to insulin resistance or age-related decline. One user noted feeling “physically present and revitalized” after years of struggling with low energy.

  • Neurological Effects: Older adults in specialized groups (e.g., those following Long Covid or macular degeneration research) have reported improvements in “brain fog” and cognitive clarity within 2–4 weeks of starting a protocol.

  • Physical Endurance: While less common as a “gym peptide,” some older users describe a tangible increase in physical stamina and “recovery speed” after 1–2 weeks of use.

  • Key Community Consensus

  • Target Population: Discussion in longevity forums suggests the most significant benefits are seen in individuals over 50 or those with high levels of reactive oxygen species (ROS).

  • Cost vs. Benefit: Many users mention that SS-31 is expensive. Some community reviews indicate that while they experienced no negative health consequences, they did not feel enough of an effect to justify the high cost unless they had significant pre-existing fatigue or mitochondrial dysfunction.

“Research highlights its ability to target mitochondrial dysfunction, a primary driver of neurodegeneration.”

Alzheimer’s Disease (AD) Research

In laboratory models of Alzheimer’s, SS-31 has shown potential to slow disease progression by protecting the brain’s energy-producing centers.

  • Amyloid-β and Tau Reduction: Long-term treatment with SS-31 in early-stage AD mouse models has been shown to lower levels of toxic amyloid-β (Aβ) and reactive oxygen species (ROS).
  • Mitochondrial Transport: AD neurons typically suffer from impaired mitochondrial movement to synapses. SS-31 has been shown to increase the “motile and anterograde movement” of mitochondria, helping them reach the synapses where energy is most needed.
  • Cognitive Improvement: Studies using various memory-impaired mouse models report that SS-31 treatment reversed cognitive and behavioral deficits, likely by restoring synaptic proteins like synaptophysin and PSD95.
  • Neurovascular Protection: It may prevent age-related vascular cognitive impairment by improving blood-brain barrier function and cerebromicrovascular dilation.

Parkinson’s Disease (PD) Research

For Parkinson’s, evidence focuses on protecting the dopamine-producing neurons that are typically lost as the disease advances.

  • Dopaminergic Neuroprotection: In the MPTP mouse model (a standard PD model), SS-31 significantly reduced the loss of dopamine-producing motor neurons and improved motor performance and survival.
  • α-Synuclein Interaction: Recent 2024 studies suggest SS-31 can displace α-synuclein from mitochondrial membranes, potentially inhibiting its toxic aggregation and reducing the impairment it causes to mitochondrial function.
  • Next-Generation Candidates: Stealth BioTherapeutics is developing bevemipretide, a next-in-class systemic compound that recently demonstrated neuroprotective effects in PD studies supported by the Michael J. Fox Foundation.

Current Status and Safety (2026)

  • FDA Approval: While not yet approved for AD or PD, the FDA granted accelerated approval to elamipretide (as FORZINITY) in September 2025 for Barth syndrome, marking it as the first approved mitochondria-targeted therapy.

Ref 1

Ref 2

Ref 3

Ref4

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#17

From my searches, that seems like a very large dosing regimen. How did you decide the dosages you are taking?

#18

A bit more info on MOTS-c

I’ve used low and high dose MOTS-c and low and high dose SS 31.

MOTS- c - 333mcg single dose - low dose daily for 2 months
MOTS-c - 10mg twice a day - high dose 20mg x 2 days per week

SS 31 - 3.33mg single per day - low dose for 30 days
SS 31 - 10mg twice per day, 20mg total per day - high dose for 5 days

In each case I only noticed a potential benefit with the high doses.

EDIT: I’m going to try MOTS-c daily with a 12.0mg x 2 = 24mg dose for 10 consecutive days. This is up from my previous high dose of 10mg x 2 per day = 20mg, only 2 days per week for 1 month.

MOTS-c activator of the PGC-1α pathway (1).pdf (569.9 KB)

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#19

Whats that expression “what does not kill me makes me stronger”. Humor aside, I knew even at 40 mgs it was safe (dosing frequency?). A YT video by Hunter Williams talked about using minimum of 10 for kidney rejuvenation and I latched on to it. I am also planning on joining Alex Kikel’s SKOOL to put my peptide journey on better footing, esp with regards to dosing, frequency and cycling. I am in my upper sixties and been a diabetic for over 20 years so there is plenty to repair though it is only now my kidneys started showing signs of distress. Cheers

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#20

Your dosage appears to be correct. On further examination the dosages used were much higher that I originally thought.

I am certainly rethinking the practicality for me to engage in SS-31 therapy after looking at the human studies. It would be beyond what I’m willing to pay. I don’t think it would be practical for me unless I set up a company and import it wholesale directly from China. This would be the only affordable way I could do it. The dosages are much higher than I originally thought.

The main fly in the ointment is that the effects are reversible.“Because SS‑31’s effects are rapid but short‑lived at the mitochondrial level.” So a single dose might help short-term, but “repeated multi‑week courses, not a finite, one‑time protocol to permanently restore mitochondrial function in the elderly.”

Ref

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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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