Exercise Mimetics Ranked: Which Ones Actually Work?
Which exercise mimetic or mitochondrial compound is actually worth taking?
Ca-AKG, urolithin A and MOTS-c tie at 6.5, and only the first two are things you can legally buy. SS-31 follows at 6.0. The bottom three score low on human evidence, not on mechanism. The compound that best mimics exercise in the exercise-relevant rows ranks last.
- Three members tie at 6.5: urolithin A, Ca-AKG and MOTS-c. Nothing in this category scores above 6.5.
- Only two of the seven are ordinary supplements. Five have no legal retail channel, and four have never been given to a human being in a published trial.
- SLU-PP-332 ranks last at 4.7 and wins four of the twelve use-case rows, including endurance and body composition. It is the only compound here designed to imitate training, and the only one Nick had a clearly negative response to.
- Ca-AKG takes five rows on the strength of one controlled human endpoint plus mouse lifespan data. Read that row carefully: the human trial measured bone-turnover markers, not lifespan.
- SS-31 has an FDA approval and the highest mitochondrial subrating at 8.5. The approval is for one rare genetic disease and does not transfer to healthy people.
- The ranking is the live score. When a member's score moves, this page moves with it.
The Ranking
7 interventions ranked by live BioHarmony score.
Rank 1: Urolithin A
6.5 / 10 Worth tryingPINK1/Parkin mitophagy inducer. Retail supplement. BioHarmony 6.5, worth trying.
Rank 1: Ca-AKG (Calcium Alpha-Ketoglutarate)
6.5 / 10 Worth tryingTied at 6.5 and the widest winner on this page, taking healthspan (7.2), longevity (7.0), anti-inflammatory (6.8), muscle growth and neuroprotection. Shahmirzadi 2020 found longer life and compressed late-life frailty in aged mice, Chin 2014 extended lifespan in C. elegans, and Filip 2007 is the one controlled human endpoint in this whole category: lower CTX bone-resorption markers in postmenopausal women over 24 weeks. Pick it over urolithin A when you want the broadest systemic case at the lowest price. The weak link is the biological-age claim everyone quotes, which comes from an uncontrolled brand-funded study of 42 users.
Krebs-cycle intermediate and epigenetic cofactor. Retail supplement. BioHarmony 6.5, worth trying.
Rank 1: MOTS-c
6.5 / 10 Worth tryingThird in the tie and the first member with no legal way to buy it. Lee 2015 identified MOTS-c as a peptide encoded in mitochondrial DNA that activates AMPK, the same energy sensor training activates, and Reynolds 2021 showed exercise induces it in humans and that it affects physical capacity in mice. It holds the highest blood-sugar subrating in the category at 6.0. Pick it over the two supplements only if you accept a research vial, because no published human trial has ever dosed exogenous MOTS-c and measured an outcome. The score is an access and evidence discount, not a verdict on the biology.
Mitochondrial-derived peptide, AMPK activator. Research vial only. BioHarmony 6.5, worth trying.
Rank 4: SS-31 (Elamipretide)
6.0 / 10 Worth tryingFourth overall and first on the row this category is named for, with a mitochondrial subrating of 8.5, the highest score any member holds anywhere on this page. It is also the only member with an FDA approval: Forzinity, granted accelerated approval in September 2025 for Barth syndrome in patients weighing at least 30 kg, on the back of a 95.9 metre six-minute-walk gain. Pick it when cardiolipin dysfunction is documented rather than assumed. It ranks below the tie group because the approval is one rare genetic disease wide, MMPOWER-3 missed both co-primary endpoints in 218 patients with mitochondrial myopathy, and self-directed use means a daily injection of gray-market material at $200 to $500 a month.
Cardiolipin-binding tetrapeptide. FDA approved for Barth syndrome only. BioHarmony 6.0, worth trying.
Rank 5: Humanin
5.5 / 10 🤷 NeutralFifth, and the clearest case on this page of a compound scored on an empty file rather than a bad one. Hashimoto 2001 cloned it from surviving neurons in an Alzheimer's brain, Muzumdar 2009 showed central dosing improved whole-body insulin sensitivity in rodents, and Yen 2020 found children of centenarians carry markedly higher circulating levels. No human interventional trial of administered humanin exists, and the largest human cohort, 693 people in Conte 2019, tied high levels to worse outcomes in the oldest old. Pick it over nothing only if you are running a tracked self-experiment and can live with a signal that points both directions.
Mitochondrial-derived peptide, cytoprotective. No human interventional trial. BioHarmony 5.5, neutral.
Rank 6: 5-Amino-1MQ
4.9 / 10 🤷 NeutralSixth, and the only compound in this category that works by mouth, which matters more than the ranking suggests. Neelakantan 2018 found obese mice lost roughly 5% of body weight with over 30% smaller fat cells through NNMT inhibition, and Neelakantan 2019 nearly doubled muscle-fibre size in aged injured mice. Every positive study injected it into a rodent while humans swallow it, and there are zero registered human trials of this or any NNMT inhibitor. Pick it over the injectables if the felt energy effect is what you are after and you dose orally at 50 to 150 mg, which is the only route with pharmacokinetic support.
Oral NNMT inhibitor. No human trial. BioHarmony 4.9, neutral.
Rank 7: SLU-PP-332
4.7 / 10 🤷 NeutralLast on the composite and the winner of four use-case rows, which is the single most useful contradiction on this page. Billon 2023 showed eight days of daily injection raised treadmill endurance and oxidative-muscle gene programs in sedentary mice, Billon 2024 extended that to fat mass and glucose handling, and Xu 2024 to cardiac function. It is the only compound here explicitly built to flip the switch endurance training flips, and it holds the top subrating for endurance (6.5), body composition (6.0), energy (5.5) and metabolic health (6.5). It scores 4.7 because there is no human trial, no human dose, no pharmacokinetic curve, ERR biology is entangled with tumour metabolism, and Nick's own two cycles ended in progressive fatigue and burnout.
Pan-ERR agonist, the literal exercise mimetic. Preclinical only. BioHarmony 4.7, neutral.
Best Pick by Use Case
| Use Case | Winner | Runner-Up | Why |
|---|---|---|---|
| Mitochondrial | SS-31 (Elamipretide) 8.5 | Urolithin A 7.0 | The highest subrating anywhere on this page, and the one row where an approved drug exists. SS-31 binds cardiolipin directly and stabilises cristae, which is repair rather than signalling. Urolithin A's 7.0 is the best score any purchasable member holds here. The two lowest, humanin at 3.2 and 5-Amino-1MQ at 3.0, are low because nothing has been measured in a person, not because the mechanism is weaker. |
| Endurance Cardio | SLU-PP-332 6.5 | Ca-AKG (Calcium Alpha-Ketoglutarate) 5.8 | The last-ranked compound wins the row the category is named after, on eight days of treadmill data in sedentary mice. That is the whole argument of this page in one line. SS-31 sits at 2.5 here despite the highest mitochondrial score, because MMPOWER-3 missed its six-minute-walk endpoint in people. Humanin is not scored for this use case. |
| Body Composition | SLU-PP-332 6.0 | MOTS-c 5.5 | Both winners are mouse results. SLU-PP-332 reduced fat mass in diet-induced obesity models and MOTS-c prevented diet-induced obesity in the discovery paper. 5-Amino-1MQ's 4.5 rests on roughly 5% weight loss in obese mice with over 30% smaller adipocytes. Nothing in this category has changed a human body composition in a published trial, and none of it substitutes for a calorie deficit. Humanin is not scored here. |
| Energy | SLU-PP-332 5.5 | Ca-AKG (Calcium Alpha-Ketoglutarate) 5.4 | A tenth of a point between them, so treat this row as a coin flip. The interesting entry is the one that loses: 5-Amino-1MQ scores 3.5 on published evidence and is the compound in this category Nick most reliably feels, within about thirty minutes of an oral dose. Subjective energy is the endpoint with the widest gap between what people report and what has been measured. |
| Metabolic Health | SLU-PP-332 6.5 | MOTS-c 6.0 | Both rest on rodent metabolic-syndrome models: improved energy expenditure and glucose handling in obese mice for SLU-PP-332, improved insulin sensitivity and diet-induced obesity measures for MOTS-c. Urolithin A scores 3.5 here, and its own systematic review found no clear anthropometric effect in humans. This row is where the mimetic idea is strongest in theory and weakest in evidence. |
| Blood Sugar | MOTS-c 6.0 | SLU-PP-332 5.5 | MOTS-c wins on AMPK-mediated glucose disposal and mouse insulin sensitivity from Lee 2015. Urolithin A's 1.0 is the lowest score in this table and it is correct: nothing in the urolithin A literature supports a glycemic effect. If blood sugar is the reason you are reading, none of these seven belongs ahead of the things that actually move it. |
| Healthspan | Ca-AKG (Calcium Alpha-Ketoglutarate) 7.2 | Urolithin A 5.0 | The widest gap on the page, 2.2 points, and the row that carries Ca-AKG's ranking. It comes from aged mice living longer with compressed frailty in Shahmirzadi 2020 plus the bone-turnover RCT in Filip 2007. Read the second one precisely: it measured CTX markers in postmenopausal women at 6 g a day, not healthspan and not fracture prevention. |
| Longevity | Ca-AKG (Calcium Alpha-Ketoglutarate) 7.0 | Urolithin A 5.0 | Mouse and worm lifespan on one side, an uncontrolled 42-person methylation-age study on the other. No member of this category has been measured against a human mortality or aging endpoint. MOTS-c's 4.0 comes from Fuku 2015, which associated a MOTS-c gene variant with exceptional longevity in Japanese centenarians, and an inherited variant is not a dosing result. |
| Anti Inflammatory | Ca-AKG (Calcium Alpha-Ketoglutarate) 6.8 | Urolithin A 5.5 | In Shahmirzadi 2020, IL-10 signalling was necessary for the mouse lifespan and frailty benefit, which is where Ca-AKG's inflammatory case comes from. Urolithin A's 5.5 rests on the immune-metabolic signal in Denk 2025. Neither has moved a disease-level inflammatory outcome in a person. |
| Muscle Growth | Ca-AKG (Calcium Alpha-Ketoglutarate) 5.2 | Urolithin A 5.0 | The tightest and least meaningful row here. Note what is missing: MOTS-c scores 3.0 partly because AMPK activation competes with the mTOR signalling hypertrophy runs on. An exercise mimetic that mimics endurance training is not automatically good for building muscle, and may work against it. Humanin is not scored for this use case. |
| Cardiovascular | SS-31 (Elamipretide) 5.5 | SLU-PP-332 5.5 | A dead heat at 5.5, so read this as a tie rather than a win. SS-31's score comes from cardiolipin biology and acute heart-failure signals, SLU-PP-332's from a mouse heart-failure model with preserved ejection fraction. No cardiovascular outcome trial has reported on any member of this category, and the highest score in the row is still only a 5.5. |
| Neuroprotection | Ca-AKG (Calcium Alpha-Ketoglutarate) 5.6 | SS-31 (Elamipretide) 5.5 | A tenth of a point apart and both preclinical. The name people expect to see at the top of this row is humanin, which was cloned from surviving neurons in an Alzheimer's brain and scores 3.0. That gap is the scoring model refusing to reward the best origin story in the category. |
At a Glance
Urolithin A
- Efficacy 2.7
- Breadth 3.0
- Evidence 2.8
- Speed 2.3
- Durability 2.5
- Bioindividuality 3.6
- Safety Risk 1.4
- Side Effects 1.4
- Cost 4.3
- Effort 1.3
- Opportunity Cost 2.0
- Dependency 1.5
- Reversibility 1.2
- Mitochondrial
- Anti Inflammatory
- Geriatric
- Muscle Growth
PINK1/Parkin mitophagy inducer. Retail supplement. BioHarmony 6.5, worth trying.
Ca-AKG (Calcium Alpha-Ketoglutarate)
- Efficacy 2.8
- Breadth 3.0
- Evidence 2.9
- Speed 2.0
- Durability 2.3
- Bioindividuality 3.2
- Safety Risk 1.8
- Side Effects 1.5
- Cost 2.2
- Effort 1.2
- Opportunity Cost 1.5
- Dependency 1.0
- Reversibility 1.2
- Geriatric
- Bone Joint
- Healthspan
- Longevity
Krebs-cycle intermediate and epigenetic cofactor. Retail supplement. BioHarmony 6.5, worth trying.
MOTS-c
- Efficacy 3.0
- Breadth 3.6
- Evidence 2.6
- Speed 2.6
- Durability 1.8
- Bioindividuality 2.6
- Safety Risk 1.3
- Side Effects 1.3
- Cost 3.0
- Effort 3.0
- Opportunity Cost 2.5
- Dependency 1.0
- Reversibility 1.2
- Mitochondrial
- Metabolic Health
- Blood Sugar
- Body Composition
Mitochondrial-derived peptide, AMPK activator. Research vial only. BioHarmony 6.5, worth trying.
SS-31 (Elamipretide)
- Efficacy 3.5
- Breadth 3.0
- Evidence 3.8
- Speed 2.0
- Durability 1.8
- Bioindividuality 2.8
- Safety Risk 2.0
- Side Effects 2.2
- Cost 3.8
- Effort 3.2
- Opportunity Cost 1.5
- Dependency 2.0
- Reversibility 1.3
- Mitochondrial
- Antioxidant
- Cardiovascular
- Neuroprotection
Cardiolipin-binding tetrapeptide. FDA approved for Barth syndrome only. BioHarmony 6.0, worth trying.
Humanin
- Efficacy 2.6
- Breadth 3.2
- Evidence 2.3
- Speed 2.6
- Durability 2.2
- Bioindividuality 3.2
- Safety Risk 2.0
- Side Effects 1.8
- Cost 2.8
- Effort 3.0
- Opportunity Cost 2.6
- Dependency 1.8
- Reversibility 1.6
- Mitochondrial
- Longevity
- Neuroprotection
- Metabolic Health
Mitochondrial-derived peptide, cytoprotective. No human interventional trial. BioHarmony 5.5, neutral.
5-Amino-1MQ
- Efficacy 3.0
- Breadth 3.2
- Evidence 1.8
- Speed 3.5
- Durability 2.5
- Bioindividuality 2.5
- Safety Risk 2.6
- Side Effects 2.2
- Cost 3.7
- Effort 2.5
- Opportunity Cost 3.0
- Dependency 1.8
- Reversibility 2.0
- Body Composition
- Energy
- Muscle Growth
- Metabolic Health
Oral NNMT inhibitor. No human trial. BioHarmony 4.9, neutral.
SLU-PP-332
- Efficacy 4.0
- Breadth 4.0
- Evidence 2.0
- Speed 4.0
- Durability 2.0
- Bioindividuality 3.0
- Safety Risk 3.5
- Side Effects 2.5
- Cost 3.0
- Effort 2.5
- Opportunity Cost 2.5
- Dependency 2.5
- Reversibility 2.5
- Mitochondrial
- Endurance Cardio
- Metabolic Health
- Body Composition
Pan-ERR agonist, the literal exercise mimetic. Preclinical only. BioHarmony 4.7, neutral.
Cost Comparison
| Intervention | Monthly Cost | Notes |
|---|---|---|
| Ca-AKG | $15 to $30 | Retail supplement, priced 2026-09-08 at the 1 g/day generic dose this report scores. The cheapest line on the table and one of only two you can buy without a vendor certificate of analysis. The branded Rejuvant formulation runs closer to $150 a month, and since the human biological-age data behind that brand is the uncontrolled Demidenko 2021, the premium is hard to defend on the evidence. |
| Urolithin A | $50 to $100 | Retail supplement, priced 2026-09-08 at 500 mg/day. This prices the branded material, which is the only form validated in the human trials. Generic urolithin A is cheaper and has documented purity and label-claim problems, so the cheaper number is not the same product. |
| SLU-PP-332 | $30 to $80 | ESTIMATE, priced 2026-09-08, research-chemical channel, at 3 to 5 mg a day oral. The second-cheapest line on the table belongs to the last-ranked compound with no human dose, which is the trap this ranking exists to describe. The real cost includes independent identity and purity testing, because there is no product standard behind the label. |
| 5-Amino-1MQ | $95 to $190 | ESTIMATE derived from the report's own $190 per 3,000 mg source pricing, checked 2026-09-08, at the 50 to 100 mg daily oral dose with pharmacokinetic support. The report's own framing is the right one: you are paying clinical-grade prices for preclinical-grade certainty, on a compound with zero human trials. |
| MOTS-c | $100 to $200 | ESTIMATE, priced 2026-09-07, research-vendor channel, at 5 to 10 mg subcutaneous three times weekly. Add syringes, bacteriostatic water and cold-chain shipping on top. No pharmacy exists, no insurance applies, and FDA has flagged the substance on the compounding-warning side. |
| Humanin | $100 to $300 | ESTIMATE, priced 2026-09-08, research-vial channel, at roughly 1 mg subcutaneous twice weekly. The report states only that a real cycle runs into the low hundreds per month, so treat this as an order of magnitude rather than a quote. Note that the marquee metabolic research used the more potent HNG analogue, which is a different molecule from what you would be buying. |
| SS-31 (elamipretide) | $200 to $500 | ESTIMATE, priced 2026-09-07, gray-market channel, at 5 to 10 mg a day. The most expensive line here, and the approved route is worse rather than better: Forzinity is priced and distributed as an ultra-rare-disease orphan drug. Higher daily doses push monthly spend into the thousands with no prescription coverage. |
| The difference | $15 to $500, and the cheap end is the legal end | Two of the seven have a real retail price: Ca-AKG at $15 to $30 and urolithin A at $50 to $100. Those are also the two highest-ranked purchasable members, which makes this category unusual. Normally the legal option costs more.Everything else on the table is an estimated research-vial or research-chemical cost, and the ordering inside that group tells you nothing about quality. SLU-PP-332 is the second-cheapest line on the page and has never been given to a human. SS-31 is the most expensive and is the only member with an FDA approval, which you almost certainly cannot use. Every figure carries a pricing date because this channel moves. |
Who Should Pick What?
You want one thing from this list and you want it to be legal
Ca-AKG (Calcium Alpha-Ketoglutarate)
It takes five of the twelve use-case rows, it is an ordinary supplement, and it is the cheapest way into this category. Track total supplemental calcium while you use it, because each gram of Ca-AKG carries roughly 200 mg of elemental calcium and Anderson 2016 supports caution around supplemental calcium and coronary artery calcification.
Older or sedentary, and muscle mitochondria are the target
Urolithin A
This is where the human trial signal actually lives. Andreux 2019 and Liu 2022 both studied older adults, and the mitochondrial subrating of 7.0 is the highest any purchasable member holds. Buy the branded material that matches the trials rather than generic urolithin A, and give it four months rather than four weeks.
Already fit, training hard, and hoping one of these adds a gear
Tie
None of the seven. The trial populations that responded were older, sedentary, injured or obese, and the compound built specifically for trained endurance has been tested in mice for eight days. Nick ran urolithin A at 500 mg a day for about 90 days from an already-fit baseline and recorded no clearly noticeable subjective effect. This is the row where the answer is to keep training.
Documented mitochondrial dysfunction with objective markers
SS-31 (Elamipretide)
An 8.5 mitochondrial subrating and the only regulatory approval in the category. Two hard qualifiers: the approval covers Barth syndrome in patients over 30 kg and nothing else, and MMPOWER-3 missed both co-primary endpoints in 218 patients with primary mitochondrial myopathy. If you have a diagnosis, this is a specialist conversation. If you do not, it is a daily injection of gray-market peptide at $200 to $500 a month.
You want the felt effect, not the biomarker
5-Amino-1MQ
It is the only member here that works orally, and the one Nick reports actually noticing, within about thirty minutes at 50 to 100 mg as a pre-workout. Understand exactly what you are buying: zero human trials, a quinolinium scaffold whose genotoxicity is unconfirmed rather than ruled out, and a WADA ban. The injectable microgram protocols sold alongside it are almost certainly too low to do anything.
You are chasing the actual exercise-mimetic idea
SLU-PP-332
It is the real thing conceptually and the worst bet practically, which is why it ranks last while winning four rows. There is no human dose, no pharmacokinetic curve, and no safety package. Nick ran two cycles and was progressively fatigued, drained and burnt out within about two weeks both times, resolving within days of stopping. Follow the ERR literature instead of buying the compound.
Insulin resistance is the reason you are here
MOTS-c
It holds the top blood-sugar subrating in the category at 6.0, on AMPK mediated glucose disposal and mouse insulin-sensitivity data. That is still a mouse. Before a research vial, the honest sequence is the things with human outcome data behind them, and MOTS-c after them rather than instead of them.
Building a longevity stack and deciding what earns a slot
Tie
Two of these seven, Ca-AKG and urolithin A, cost less than a month of most peptides and can be bought without a vendor certificate of analysis. The other five ask you to inject unapproved material for signals measured in worms, mice and cell culture. Take the two that are supplements, skip the five that are not, and revisit when a human trial publishes.
How This Ranking Is Built
- Ranked by
- the live BioHarmony overall score
- What is included
- Every published BioHarmony intervention report whose primary mechanism is activation of a pathway that endurance training activates, or direct repair of the mitochondria that training remodels. That covers the mitochondrial derived peptides encoded in mitochondrial DNA, direct agonists of the transcriptional machinery behind mitochondrial biogenesis, mitophagy inducers, and compounds that stabilise the inner mitochondrial membrane. Substrate and cofactor repletion is out, which is why the NAD precursors and CoQ10 are excluded despite sharing the search cluster. Exercise itself is out. Adding a new report inside this boundary adds a row.
- Kept current
- Positions and scores are read live from each intervention report on every page load, so the order re-renders the moment any member is rescored. Membership is rebuilt nightly against the inclusion rule above.
The order on this page is the live BioHarmony overall score, read from each member's report when the page renders. It is not an editorial ranking, and nothing about it is fixed. When a member's score changes, the row moves that night.
Three members tie at 6.5. Within the tie the order is by upside total, the sum of the benefit dimensions before risk is subtracted: urolithin A 1.845, Ca-AKG 1.785, MOTS-c 1.770. Those are hundredths apart. That is a tiebreak, not a ranking, and the three should be read as equivalent.
What the score measures is the part most rankings skip. The BioHarmony overall combines effect size with evidence quality, safety, access, cost and practicality. A compound with a beautiful mechanism that can only be bought as a research vial scores below an ordinary supplement with a smaller effect, and that is deliberate. It is the whole reason SLU-PP-332, the only compound here designed from the ground up to imitate endurance training, sits last while winning four of the twelve use-case rows.
Two facts about this category matter more than the ordering. Five of the seven have no legal retail channel. And four of the seven, MOTS-c, humanin, 5-Amino-1MQ and SLU-PP-332, have never been administered to a human being in a published trial. Every score they carry is extrapolated from cells, rodents or correlations. Only urolithin A, Ca-AKG and SS-31 have human interventional data of any kind, and Ca-AKG's amounts to one controlled endpoint measuring bone-turnover markers.
The use-case table uses twelve rows drawn from the subratings the members share. Four of the seven carry a full 66-use-case subrating set; humanin is scored across 15 use cases and 5-Amino-1MQ across 22, so humanin is absent from the endurance, body composition and muscle growth rows. Where a member is not scored for a use case the note says so, rather than letting a blank read as a zero.
Costs in the table are ESTIMATES with a pricing date except where a retail product exists, and for the research-vial members they are the price of material sold not for human use with vendor-dependent purity. Treat them as channel estimates, not quotes.
Research Highlights
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Mechanism Difference
Four different mechanisms sit under the phrase exercise mimetic and they are not interchangeable. MOTS-c and humanin are peptides your own mitochondria encode and secrete, discovered in mitochondrial DNA rather than designed: MOTS-c is the metabolic, AMPK-activating half of that family and humanin the cytoprotective half. SLU-PP-332 is the only true designed mimetic, a synthetic pan-ERR agonist built to flip the transcriptional switch endurance training flips.Urolithin A works one layer down, inducing PINK1 and Parkin-dependent mitophagy so damaged mitochondria are cleared rather than stimulated. SS-31 works one layer down again, binding cardiolipin in the inner membrane to hold cristae together, which is structural repair rather than signalling. Ca-AKG is a Krebs-cycle intermediate that doubles as an epigenetic cofactor, and 5-Amino-1MQ blocks NNMT to spare methyl groups and nicotinamide. Reading this list as one idea getting progressively better misses the point entirely. These are six different bets on what part of exercise is worth copying.
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Evidence Maturity
The most useful number on this page is not the top score. It is that four of the seven members have never been administered to a human being in a published trial. MOTS-c, humanin, 5-Amino-1MQ and SLU-PP-332 carry subratings built entirely from cell culture, rodents and correlation.Of the three that do have human data, the depth varies more than the scores suggest. Urolithin A has genuine randomised trials, sponsor-funded and with missed primary endpoints, but real. SS-31 has an entire multi-indication clinical programme and an FDA approval, and also two large negative readouts. Ca-AKG has exactly one controlled human endpoint, a 24-week bone-turnover-marker trial in postmenopausal women at 6 g a day, plus an uncontrolled 42-person methylation-age study that its own report calls the weak link. That is what the top of this ranking is built on. It is more than the bottom has, and it is much less than the marketing implies.
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Safety Comparison
There is no class-wide contraindication here, because these seven are not a class. What repeats across the reports is the sourcing risk rather than the pharmacology: five of the seven name unverified vials or unverified product as a reason not to proceed, and for the four with no human data that procurement risk is larger than any documented effect of the molecule itself.The compound-specific cautions are where the mechanisms show. Humanin is pro-survival and engages the IGFBP-3 axis, so its report flags active or suspected cancer as a real theoretical concern. SLU-PP-332 carries the same shape of flag for a different reason, because ERR biology is entangled with tumour metabolism. 5-Amino-1MQ sits in a quinolinium chemical family that includes known mutagens and its genotoxicity is unconfirmed rather than ruled out. SS-31 has an actual drug label with actual boundaries: serious hypersensitivity, a benzyl-alcohol neonatal warning, renal dose adjustment. Ca-AKG's caution is the least exotic and the most likely to apply to you, which is the elemental calcium load.
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Cost Comparison
The price spread in this category runs roughly ten to one, and it does not track the ranking. The two cheapest routes are the two ordinary supplements at the top, which is unusual and worth saying plainly: here, the legal option is also the cheap option.The expensive end is SS-31, at $200 to $500 a month for gray-market material at 5 to 10 mg a day, and higher still through the approved orphan-drug channel that most readers cannot use anyway. The oddity is 5-Amino-1MQ, where an eight-week oral cycle at the top of the dose range runs several hundred dollars for a compound with zero human trials. You are paying clinical prices for preclinical certainty. Every figure here carries a pricing date because the research-vial channel moves.
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Editorial Verdict
For most people the answer in this category is Ca-AKG or urolithin A, and which one depends on whether you want the broadest systemic case or the one with the most direct muscle-mitochondria evidence. Both are supplements, both cost less than a month of any peptide here, and both have something human behind them.The other five are worth understanding and mostly not worth buying. SS-31 is a real drug with a real approval that is not for you unless you have a diagnosis. MOTS-c and humanin are legitimate endogenous signals with empty human files. 5-Amino-1MQ is the one with a genuine felt effect and the least evidence to explain it. And SLU-PP-332 is the most conceptually exciting compound on this page, the winner of four use-case rows, and the one where the recorded personal experience was clearly negative twice. None of that is a reason to buy a vial labelled not for human use.
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Ranking Stability
This ranking is not an opinion that gets refreshed quarterly. The order is the live BioHarmony overall score for each member, resolved when the page loads, so a rescoring of any one report reorders the page that night without an editorial pass.Expect movement, and expect it from a specific direction. The gap between first and last is 1.8 points, and four members sit near the bottom entirely because their evidence column is empty. A single clean human trial on any of those four would raise evidence quality and plausibly efficacy at the same time, which is the combination that produces a large score change. Each of those reports names its own trigger: a Phase 2 confirming oral fat loss for 5-Amino-1MQ, a first human interventional trial for humanin, a Phase 1 safety and pharmacokinetic package for SLU-PP-332. None of them has happened yet.
Frequently Asked Questions
- What is the best exercise mimetic?
- On the BioHarmony score, three tie at 6.5: urolithin A, Ca-AKG and MOTS-c. Only the first two can be legally bought. If the question means which one most closely imitates endurance training, the answer is SLU-PP-332, which is designed to do exactly that and ranks last at 4.7 because it has never been given to a person in a published trial.
- Does any of this replace exercise?
- No, and nothing in these seven reports claims it does. The best endurance evidence in the category is eight days of treadmill data in sedentary mice. Every human trial that showed anything studied older, sedentary or injured populations, which is the group furthest from trained. The honest framing is a possible adjunct to training for specific people, not a substitute for it.
- Why does SLU-PP-332 rank last if it wins four use cases?
- Because the score weighs more than effect size. SLU-PP-332 holds the top subrating for endurance, body composition, energy and metabolic health, and it still scores 4.7. It has no human trial, no validated human dose, no pharmacokinetic curve and no safety package, ERR biology is entangled with tumour metabolism, and it is sold as a research chemical. Those facts pull four winning rows down to last place.
- Is MOTS-c or SS-31 better?
- MOTS-c scores 6.5 and SS-31 6.0, but they do different jobs. SS-31 holds the highest mitochondrial subrating in the category at 8.5 and is the only member with an FDA approval, though that approval covers Barth syndrome and nothing else. MOTS-c holds the highest blood-sugar subrating. Nick has run both and describes MOTS-c as the software upgrade and SS-31 as the hardware upgrade, and reports noticing more from MOTS-c.
- Which one is cheapest?
- The two supplements at the top of the ranking, Ca-AKG and urolithin A, are the cheapest legal routes into this category. That is unusual and worth saying plainly: here the legal option is also the cheap one. The expensive end is SS-31 at $200 to $500 a month for gray-market material, and 5-Amino-1MQ, where an eight-week oral cycle at the top of the dose range costs several hundred dollars for a compound with zero human trials.
- Are the research-vial versions the same compound?
- There is no way to know from the label. Five of the seven have no legal retail channel, so the real-world supply is material sold not for human use, with no product standard behind it and vendor-dependent purity. All five of those reports name unverified product as a reason not to proceed. Purity verification is not an optional extra on that channel, and it is part of why those members score low on access regardless of their preclinical data.
- How often does this ranking change?
- Whenever any member's score changes. The order is the live BioHarmony overall pulled from each report at render time, and a rescoring reorders the page that night with no editorial pass. Four of the seven sit near the bottom entirely because their human-evidence column is empty, so a single clean trial on any of them would move this list.
- Should I stack these?
- The reports name two pairings and neither is tested. MOTS-c and humanin are the metabolic and cytoprotective halves of the same peptide family and are commonly run together, and Nick's own note is that MOTS-c works best after an SS-31 cycle. Both are community practice, not trial evidence. Stacking two compounds with no human data does not produce one compound with human data.
Evidence Sources
- Animal study The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance (2015) Discovery paper. MOTS-c is encoded in mitochondrial 12S rRNA and activates AMPK by inhibiting ATIC and raising AICAR. Improved insulin sensitivity and diet-induced obesity measures in mice.
- Animal study MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis (2021) Exercise induces endogenous MOTS-c in humans, and MOTS-c affected late-life physical capacity in mice. Endogenous exercise response is not the same as exogenous dosing.
- Meta-analysis Circulating MOTS-c levels across metabolic states: a biomarker meta-analysis (2024) Pooled human biomarker studies showing circulating MOTS-c differs by metabolic state. Measures associations, not outcomes after dosing.
- Cohort study A mitochondrial-derived peptide variant and exceptional longevity in Japanese centenarians (2015) Associated the K14Q MOTS-c variant with exceptional longevity. An inherited variant, not a result of taking the peptide.
- Regulatory FDA: certain bulk drug substances for use in compounding may present significant safety risks (2026) FDA lists MOTS-c among bulk substances flagged for compounding safety risk. There is no legal compounding pathway for it.
- RCT The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans (2019) First-in-human trial. Four weeks of oral urolithin A shifted plasma acylcarnitines and skeletal-muscle mitochondrial gene expression in older adults, with favourable short-term tolerability.
- RCT Effect of urolithin A supplementation on muscle endurance and mitochondrial health in older adults (2022) Adults aged 65 to 90. Muscle-endurance and biomarker improvements, but six-minute walk distance and maximal ATP production were not clearly significant versus placebo.
- Systematic review Urolithin A in human health: a systematic review (2024) Five human studies in 250 healthy individuals. Mitochondrial, autophagy and inflammation signals, but no clear effect on cardiovascular outcomes, anthropometrics, gut microbiota or broad physical function.
- RCT Urolithin A and immune aging: a four-week human study (2025) Four-week immune-aging signal with naive-like CD8+ cell expansion and improved immune-cell fatty-acid oxidation.
- Animal study Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents (2016) The foundational preclinical signal: lifespan extension in worms and muscle-function gains in rodents through induced mitophagy.
- Observational Urolithin metabotypes: interindividual variability in urolithin production from dietary ellagitannins (2017) Adults differ substantially in the ability to make urolithin A from dietary ellagitannins, so many people are low or non-producers regardless of intake.
- Animal study Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice (2020) Aged mice fed Ca-AKG lived longer with compressed late-life frailty. IL-10 signalling was necessary for the effect. The strongest anchor behind Ca-AKG's healthspan and longevity subratings.
- Animal study The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR (2014) AKG extended lifespan in C. elegans through ATP synthase and TOR inhibition, giving a second species and a coherent mechanism.
- RCT Alpha-ketoglutarate decreases serum levels of C-terminal cross-linking telopeptide of type I collagen in postmenopausal women (2007) The one controlled human endpoint in this category. 6 g/day AKG plus calcium lowered CTX bone-resorption markers over 24 weeks in postmenopausal osteopenic women. Markers, not fractures.
- Observational Rejuvant, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging (2021) 42 users, large reported methylation-age improvement. Uncontrolled, brand-funded and vitamin-confounded. The weakest link in Ca-AKG's file and the most quoted.
- Cohort study Calcium intake from diet and supplements and the risk of coronary artery calcification (MESA) (2016) Does not test Ca-AKG, but supports caution around supplemental calcium and coronary artery calcification. Relevant because each gram of Ca-AKG carries roughly 200 mg of elemental calcium.
- Animal study The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin (2013) Mechanism paper. SS-31 binds cardiolipin, protects cristae membranes and accelerates ATP recovery after ischemia in preclinical kidney models.
- RCT Efficacy and safety of elamipretide in primary mitochondrial myopathy: MMPOWER-3 randomized clinical trial (2023) 218 patients. Missed both co-primary endpoints, the six-minute walk test and fatigue. The largest negative readout in this category.
- RCT Long-term elamipretide treatment in Barth syndrome: open-label extension (2021) A 95.9 metre six-minute-walk gain in open-label extension. The clinical evidence behind the FDA accelerated approval.
- Regulatory FDA grants accelerated approval to first treatment for Barth syndrome (2025) Forzinity (elamipretide) approved September 2025 for Barth syndrome in patients weighing at least 30 kg. The only regulatory approval held by any member of this category, and it is one rare disease wide.
- RCT Elamipretide in dry age-related macular degeneration: ReCLAIM-2 randomized trial (2024) Missed primary endpoints in dry AMD, with adverse events more frequent than placebo and mainly injection-site reactions.
- In vitro A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta (2001) Humanin cloned from an Alzheimer's brain; abolished neuronal death from a wide spectrum of familial Alzheimer's insults in cells.
- Animal study Humanin: a novel central regulator of peripheral insulin action (2009) Central humanin improved whole-body insulin sensitivity through hypothalamic STAT3 in rodents. The marquee metabolic work leaned on the more potent HNG analogue.
- Observational Humanin prevents age-related cognitive decline and correlates with lifespan (2020) Children of centenarians carry markedly higher circulating humanin than age-matched controls, and levels decline with age. The single most cited reason people find this peptide interesting.
- Cohort study Human aging and longevity are characterized by high levels of mitokines (2019) 693-person cohort. High circulating humanin was tied to worse outcomes in the oldest old, pointing the opposite way to the centenarian-offspring story.
- Animal study Selective inhibition of nicotinamide N-methyltransferase reduces adiposity in diet-induced obese mice (2018) Obese mice lost roughly 5% of body weight with over 30% smaller fat cells, driven by increased fat burning rather than reduced appetite. The single strongest 5-Amino-1MQ finding, and it is a mouse.
- Animal study Nicotinamide N-methyltransferase inhibition enhances regeneration in aged skeletal muscle (2019) Nearly doubled muscle-fibre size and raised peak torque after injury in aged mice. The benefit appeared only in aged or injured animals.
- Animal study NNMT inhibition improves grip strength in aged mice (2024) About 40% higher grip strength in aged mice, adding a second independent aged-muscle signal for NNMT inhibition.
- Animal study 1-Methylnicotinamide and vascular function (2012) The basis for the concern that chronically suppressing the metabolite 1-MNA could carry a cardiovascular cost. The reason 5-Amino-1MQ's safety score stays elevated despite no proven toxicity.
- Animal study Synthetic ERR agonist SLU-PP-332 increases exercise capacity in mice (2023) Eight days of daily intraperitoneal dosing raised treadmill endurance and oxidative-muscle gene programs in sedentary mice. The core study, and the corrected PubMed record after the original v0 citation pointed at an unrelated paper.
- Animal study ERR agonism in diet-induced obesity: metabolic-syndrome improvements in mice (2024) Improved energy expenditure, reduced fat mass and better glucose handling in obese mouse models over several weeks.
- Animal study SLU-PP-332 and SLU-PP-915 in a mouse model of heart failure (2024) Enhanced cardiac fatty-acid oxidation, preserved ejection fraction and reduced fibrosis, on high-dose regimens that may not translate safely.
- In vitro Estrogen-related receptor alpha and tumour metabolism (2002) ERR biology is intertwined with tumour metabolism. Does not show SLU-PP-332 causes cancer; shows the pathway is not harmless background biology to manipulate chronically.
- Regulatory WADA prohibited list (2026) MOTS-c and 5-Amino-1MQ are banned in tested sport, and SLU-PP-332 is of active doping-control interest. Relevant to any competing athlete reading this ranking.
Glossary
Quick reference for the medical and technical terms used in this comparison.
- AMPK AMP-Activated Protein Kinase
- The cell's energy sensor, switched on by exercise and caloric stress. MOTS-c activates it, which is the entire basis of the exercise-mimetic claim for that peptide.
- ERR Estrogen-Related Receptor
- A family of orphan nuclear receptors that work with PGC-1 alpha to control mitochondrial biogenesis and oxidative muscle-fibre programs. SLU-PP-332 is a synthetic agonist of all three.
- MDP Mitochondrial-Derived Peptide
- A peptide encoded inside mitochondrial DNA rather than the nucleus. MOTS-c and humanin are the two in this ranking; MOTS-c is the metabolic half of the family and humanin the cytoprotective half.
- Mitophagy Selective mitochondrial autophagy
- The quality-control process that clears damaged mitochondria. Urolithin A induces it through the PINK1 and Parkin pathway, which is cleanup rather than stimulation.
- Cardiolipin Inner mitochondrial membrane phospholipid
- The lipid that organises cristae, the folds where the electron transport chain sits. SS-31 binds it directly, and Barth syndrome is a genetic failure to remodel it.
- NNMT Nicotinamide N-Methyltransferase
- An enzyme that consumes nicotinamide and methyl groups. 5-Amino-1MQ blocks it, sparing both, which is the proposed route to its fat and muscle effects.
- AKG Alpha-Ketoglutarate
- A Krebs-cycle intermediate that also acts as a cofactor for the enzymes that demethylate DNA. Sold as the calcium salt, which is where the elemental calcium load comes from.
- CTX C-terminal telopeptide of type I collagen
- A blood marker of bone resorption. The endpoint that moved in Filip 2007, and the only controlled human result in this entire category.
- PGC-1 alpha Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
- The master regulator of mitochondrial biogenesis, and the switch endurance training flips. Every compound on this page is trying to reach it or its downstream effects by a different route.
- 6MWT Six-Minute Walk Test
- How far someone walks in six minutes. The functional endpoint SS-31 gained 95.9 metres on in Barth syndrome and missed in mitochondrial myopathy, and that urolithin A missed in older adults.
- Metabotype Urolithin producer status
- Whether your gut bacteria can convert dietary ellagitannins into urolithin A. Many people cannot at all, which is the main argument for supplementing the finished molecule.
- Preclinical Before human testing
- Cells and animals. Four of the seven members here have nothing else, which is the single fact that most explains the shape of this ranking.
First inside the three-way tie on upside total, and the only member of this category with a proper first-in-human trial behind it. Andreux 2019 showed measurable acylcarnitine and skeletal-muscle mitochondrial gene-expression shifts after four weeks of oral dosing, and Liu 2022 found muscle-endurance and biomarker gains in adults aged 65 to 90. Pick it over Ca-AKG when the target is muscle mitochondria specifically and you are older or sedentary, which is where the trial signal lives. The honest caveat is that the same trials missed their headline functional endpoints, and every flagship study is sponsor-funded.