Mitochondria have long been relegated to the role of the cell’s “powerhouse,” but a comprehensive review by Iñigo San Millán at the University of Colorado (USA), published in the journal Antioxidants (2023), argues they are actually the central negotiators of human health and longevity. The “Big Idea” presented by Iñigo San-Millán is that mitochondrial dysfunction is not merely a symptom of aging but the primary pathogenic driver behind the modern epidemic of non-communicable diseases (NCDs), including Type 2 Diabetes, Alzheimer’s, and various cancers.
The paper shifts the focus from downstream metabolic markers (like blood glucose) to the upstream bioenergetic capacity of the mitochondria. When mitochondria lose the ability to efficiently oxidize substrates—particularly lactate and fatty acids—the resulting metabolic inflexibility triggers a cascade of oxidative stress and systemic inflammation. This “bioenergetic failure” precedes clinical diagnosis by years, suggesting that mitochondrial health is the ultimate biomarker for “biological age”.
The review synthesizes decades of data to show that the metabolic characteristics of elite athletes—marked by high mitochondrial density and “metabolic flexibility”—represent the gold standard for disease prevention. Conversely, the “sedentary phenotype” results in a “clogged” electron transport chain, leading to the accumulation of reactive oxygen species (ROS) that damage cellular DNA and proteins. This bioenergetic collapse is increasingly viewed as the “common denominator” in aging.
Source:
Open Access Paper: The Key Role of Mitochondrial Function in Health and Disease
The impact score (JIF) of this journal is 6.6, and its CiteScore is 12.4Antioxidants MDPI Journal Spotlight (2025). Evaluated against a typical high-end range of 0–60+ for top-tier general science (e.g., Nature or Science), this is a High-impact specialty journal, particularly dominant in the fields of Biochemistry and Physiology where it consistently ranks in the first quartile (Q1).
Part 2: The Biohacker Analysis
Study Design Specifications:
Type: Narrative and Systematic Literature Review (Synthesizing both In vivo and clinical data).
Subjects: Humans (ranging from sedentary individuals to professional athletes) and various murine models (C57BL/6J).
Mechanistic Deep Dive:
Lactate Shuttling: The paper identifies lactate as a major signaling molecule and fuel source. Dysfunctional mitochondria fail to clear lactate, leading to “lactate-induced” metabolic gridlock San-Millán (2023).
Mitochondrial Dynamics: Focuses on the balance of mitophagy (clearance of damaged units) and biogenesis (creation of new ones). Exercise is highlighted as the most potent activator of the PGC-1α pathway, the master regulator of mitochondrial biogenesis Exercise-Induced Benefits for Mitophagy (2021).
Metabolic Flexibility: The ability to switch between lipid and carbohydrate oxidation is lost in the aging/sedentary phenotype, leading to “mitochondrial gridlock” and insulin resistance.
Novelty:
The review formalizes the concept that Cardiorespiratory Fitness (CRF) is effectively a proxy for mitochondrial health. It argues for “Metabolic Rehabilitation” through specific Zone 2 exercise protocols to restore mitochondrial function as a primary treatment for chronic disease, rather than just managing symptoms with pharmaceuticals.
Critical Limitations:
Translational Gap: Much of the molecular mapping of the electron transport chain relies on murine tissue; human metabolic flexibility is more complex and influenced by a wider array of lifestyle variables.
Methodological Weakness: The review is heavily focused on exercise as the primary modality, potentially under-analyzing the role of pharmacological mitochondrial enhancers (e.g., Urolithin A, NAD+ precursors) UA and NR in Microglial Cells (2024).
Missing Data: Precise “dose-response” curves for exercise-induced mitochondrial biogenesis in elderly populations remain poorly defined.
Safety Check: High-dose NR (1,200 mg/kg in rats) showed no major toxicity, but human long-term safety above 1-2g/day is not fully established Safety Assessment of NR-E (2020).
Part 4: Actionable Intelligence
The Translational Protocol:
Human Equivalent Dose (HED): If using compounds like NR based on rat studies (e.g., 300 mg/kg), the HED for a 70kg human is ~3,400 mg.
Sourcing: Urolithin A and NR are commercially available; purity should be verified via 3rd-party COAs.
Part 5: Strategic FAQ
Can metformin blunt the mitochondrial adaptations of exercise? Yes, preliminary RCT data suggests metformin may inhibit the mitochondrial biogenesis normally triggered by aerobic exercise in older adults.
What is the “Gold Standard” for measuring mitochondrial function in vivo? 31P Magnetic Resonance Spectroscopy (MRS) allows for non-invasive measurement of ATP synthesis and phosphocreatine recovery San-Millán Review (2023).
Does the paper advocate for high-intensity interval training (HIIT)? It acknowledges HIIT for “maximal power,” but prioritizes Zone 2 for “metabolic base” and lipid oxidation efficiency.
Are there contraindications for mitochondrial antioxidants? Excessive supplementation (e.g., high-dose Vitamin E/C) can actually blunt beneficial “mitohormetic” signaling from exercise.
How does cGAS-STING relate to mitochondrial health? Leaky mitochondrial DNA (mtDNA) into the cytoplasm triggers the cGAS-STING pathway, causing sterile inflammation (inflammaging) UA and cGAS-STING (2024).
Is lactate clearance a viable biohack? Monitoring blood lactate during training (target <2.0 mmol/L) is a direct proxy for mitochondrial aerobic capacity.
What is the role of CoQ10? It is essential for electron transport; however, supplemental efficacy varies wildly by formulation (Ubiquinol vs. Ubiquinone).
Does “mitophagy” decrease with age? Yes, the accumulation of “zombie” mitochondria is a hallmark of the aging phenotype.
Can diet alone fix mitochondria? Caloric restriction (CR) and ketogenic diets can improve efficiency, but exercise remains the only known way to significantly increase mitochondrial volume.
What data is still missing? Longitudinal human data linking specific mitochondrial “scores” to actual lifespan (years lived) is currently absent. [Confidence: Medium]
To what degree might the peptide SS-31 mitigate the age-related mitochondrial dysfunction that is mentioned in the previous paper?
Gemini Pro
SS-31 (Elamipretide): The “Molecular Stent” for Mitochondrial Gridlock
Based on the mechanistic failures identified in the San-Millán paper—specifically “bioenergetic gridlock” and the inability to oxidize substrates—the peptide SS-31 (Elamipretide) represents a high-precision, pharmacological countermeasure.
While San-Millán advocates for “Zone 2” training to remodel mitochondria through biogenesis (making more mitochondria), SS-31 works by optimizing the efficiency of the mitochondria you already have. It acts as a structural stabilizer for the inner mitochondrial membrane (IMM), effectively serving as a “molecular stent” to unclog the electron transport chain.
Here is an analysis of to what degree SS-31 mitigates the specific dysfunctions cited in the paper:
1. The Core Mechanism: Unclogging the Electron Transport Chain
San-Millán describes a “clogged” metabolic state where electrons cannot flow efficiently to Oxygen, leading to lactate buildup and ROS generation. SS-31 directly addresses this structural failure.
The Target: SS-31 binds exclusively to Cardiolipin (CL), a phospholipid unique to the IMM that acts as the “glue” holding the Electron Transport Chain (ETC) supercomplexes together.
The Fix: In aging, Cardiolipin becomes oxidized and creates “gaps” in the chain, causing electron leaks (ROS) and reduced ATP. SS-31 stabilizes Cardiolipin, tightening the supercomplexes.
The Result: This “tightening” restores electron flow, directly mitigating the “gridlock.” In aged human skeletal muscle, a single infusion of SS-31 was shown to restore **** (maximal ATP production) to levels comparable to younger adults In vivo mitochondrial ATP production is improved after a single dose (2021).
2. Mitigation of Specific “San-Millán” Dysfunctions
Dysfunction (San-Millán)
SS-31 Mitigation Potential
Evidence Level
“Metabolic Gridlock” (Inability to process fuel)
High. By optimizing the ETC, SS-31 restores the electrochemical gradient required to pull substrates (like fatty acids and lactate) into the mitochondria for oxidation.
Level B (Human In Vivo Data)
Lactate Accumulation
Moderate. Rat models of ischemic stress show SS-31 significantly lowers blood lactate levels, suggesting it restores aerobic respiration capacity, the exact goal of Zone 2 training.
Very High. Unlike standard antioxidants (Vitamin C/E) which indiscriminately scavenge ROS, SS-31 prevents ROS at the source (Electron Leak) without blunting necessary signaling. This directly stops the “sterile inflammation” San-Millán links to cancer and diabetes.
Level B (Human/Mouse Consensus)
Loss of Mitochondrial Mass
Low.Critical Distinction: SS-31 improves quality (efficiency per mitochondrion) but does not induce biogenesis (quantity). It will not replace the volume-building effects of exercise.
Level D (Murine Data)
3. The Translational Gap: “Quality vs. Outcome”
While the mechanistic match is nearly perfect, the clinical reality is nuanced.
The Failure: In the Phase 3 MMPOWER-3 trial for Primary Mitochondrial Myopathy (PMM), Elamipretide failed to significantly improve the 6-Minute Walk Test (6MWT) compared to placebo, despite its success in Phase 2 MMPOWER-3 Trial Results (2023).
The Takeaway: There may be a threshold where “fixing” the electron transport chain pharmacologically is not enough to overcome severe systemic muscle atrophy (sarcopenia) without the mechanical stimulus of resistance or Zone 2 training.
Summary Verdict
SS-31 is likely the most potent pharmacological tool currently available to reverse the bioenergetic efficiency defects described by San-Millán. However, it is a partial mimetic: it restores the “engine tuning” (efficiency) but does not build a “bigger engine” (biogenesis) like exercise does.
Best Use Case: As a “primer” to restore mitochondrial function in sedentary/elderly individuals before engaging in a Zone 2 program, allowing them to exercise without immediate metabolic failure.
Both SS‑31 (Elamipretide) and GLYNAC (Glycine + NAC) work to improve mitochondrial function, but they do so through different mechanisms. SS‑31 repairs mitochondria structurally and improves energy production, while GLYNAC enhances mitochondrial performance by improving the antioxidant environment and metabolic efficiency. Both ultimately support better mitochondrial function, just through different pathways. If a person take SS-31, then the need for GLYNAC might be reduced.
An infographic for the report below “Advanced Mitochondrial Resuscitation: A Technical Analysis of SS-31 Synergies and Bioenergetic Therapeutics for Age-Related Decline”
(Note: Click on image to make it larger, then you can arrow key through all the images)
Note: just the initial part of the prompt, a small part of a multi-page prompt)
Role: You are a Longevity Research Analyst and Science Journalist. Your audience consists of scientifically literate longevity biohackers, and clinicians.
Task: Identify, analyze and summarize the scientific and clinical evidence on chemicals, drugs and supplements that support or improve measureable health metrics related to mitochondria and that might be used in parallel with the SS-31 peptide to help combat the age-related decline in mitochondrial function and biogenesis. Create a list of all effective chemicals, drugs and supplements that are effective in this goal, and prioritize the compounds used on the quality of the evidence.
Advanced Mitochondrial Resuscitation: A Technical Analysis of SS-31 Synergies and Bioenergetic Therapeutics for Age-Related Decline
Mitochondrial dysfunction is a central pillar of the aging process, characterized by a progressive failure in the capacity of cells to generate adenosine triphosphate (ATP) while simultaneously experiencing an increase in the production of damaging reactive oxygen species (ROS). The structural integrity of the inner mitochondrial membrane (IMM) is the literal foundation upon which cellular respiration occurs. As organisms age, the unique phospholipid cardiolipin, which is found exclusively in the IMM, undergoes significant peroxidation and depletion. This structural decay leads to the destabilization of respiratory supercomplexes, the opening of the mitochondrial permeability transition pore (mPTP), and the eventual initiation of apoptotic signaling. The tetrapeptide SS-31 (elamipretide) has emerged as a groundbreaking structural intervention that specifically targets and stabilizes cardiolipin. However, because mitochondrial decline is a multi-factorial event involving nutrient-sensing pathways, cofactor depletion, and the failure of quality control mechanisms like mitophagy, a singular focus on SS-31 is likely insufficient for total bioenergetic restoration. This report identifies and analyzes the clinical and scientific evidence for chemicals, drugs, and supplements that may be utilized in parallel with SS-31 to achieve a synergistic rejuvenation of mitochondrial function and biogenesis.
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.
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
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!
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
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:
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).
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!
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.
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.
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
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.”
