NAD+ vs SS-31
NAD+ is a redox cofactor and enzyme substrate for sirtuins, PARPs and CD38 whose tissue concentrations fall with age in preclinical models; because NAD+ itself is poorly absorbed orally, almost all human work uses the precursors nicotinamide riboside and nicotinamide mononucleotide. SS-31, also called elamipretide or MTP-131, is a synthetic mitochondria-targeted tetrapeptide that binds cardiolipin in the inner mitochondrial membrane and stabilises cristae architecture. They are compared because both are described as mitochondrial interventions, and unusually for this library direct evidence exists: at least three published experiments gave both an NAD+ precursor and elamipretide within one design, alone and in combination. All of them are mouse studies, and neither compound has an unblemished clinical record, so the comparison is not a case of one working and the other not.
They have been compared directly.
Three published mouse experiments administered both compounds within a single design. Whitson and colleagues treated old mouse hearts with SS-31, NMN, or both, and reported that SS-31 partially reversed an age-related decline in diastolic function while NMN fully reversed an age-related deficiency in systolic function at a higher workload; both normalised PCr/ATP dynamics under increased workload, only NMN raised NAD+ in response to increased work, and only the combined treatment produced significantly greater steady-state NAD(H). A follow-up proteomic and acetylomic study in aged mouse hearts reported that both drugs had a modest effect on restoring the abundance and acetylation of age-altered proteins while also inducing additional changes. A 2026 study in a mouse middle cerebral artery occlusion and reperfusion model reported that co-administration attenuated post-ischaemic brain damage markedly more than either monotherapy, acting through suppression of NF-kappaB and TREM2 signalling. Every one of these used NMN, a precursor, rather than NAD+ itself, and all are rodent experiments with tissue and functional endpoints in specific injury or ageing models, so they do not establish a ranking that transfers to humans or to any clinical outcome.
The 3 studies that tested both
- 01Animal in vivo2020
SS-31 and NMN: Two paths to improve metabolism and function in aged hearts
Whitson JA, et al. · Aging Cell · old mouse hearts treated with SS-31, nicotinamide mononucleotide, or the two combined, assessed by echocardiography, metabolomics and a magnetic resonance spectroscopy approach measuring metabolite response to changing cardiac workload
SS-31 partially reversed an age-related decline in diastolic function while NMN fully reversed an age-related deficiency in systolic function at higher workload. Both NMN and the combined treatment raised nicotinamide and 1-methylnicotinamide, indicating greater NAD+ turnover, but only the combination produced significantly greater steady-state NAD(H). Both agents normalised PCr/ATP dynamics under increased workload, and only NMN increased NAD+ in response to increased work. The authors concluded that both restored different aspects of mitochondrial and heart health and that combining them acted synergistically in this model.
- 02Animal in vivo2022
Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment
Whitson JA, et al. · GeroScience · aged mouse hearts analysed for protein abundance and acetylation after treatment with elamipretide or nicotinamide mononucleotide, with echocardiographic diastolic and systolic function measures
Both drugs had a modest effect on restoring the abundance and acetylation of proteins altered with age, while also inducing additional changes not seen in young hearts. Age-related increases in protein acetylation were predominantly in mitochondrial pathways including oxidative phosphorylation and TCA cycle signalling. A subset of muscle, mitochondrial and structural protein changes was associated with diastolic function in old hearts.
- 03Animal in vivo2026
Elamipretide (SS-31) and Nicotinamide Mononucleotide (NMN) Combination Therapy Targets TREM2 to Mitigate Post-ischemic Brain Injury in Mice
Yang Q, et al. · Neurochemical Research · male mice subjected to middle cerebral artery occlusion and reperfusion, treated with SS-31, nicotinamide mononucleotide, or the combination; neurobehavioural scoring, histopathology, transcriptomic sequencing, TREM2 overexpression and NF-kappaB inhibition experiments
Co-administration attenuated post-ischaemic brain damage and neurological deficits markedly more than either monotherapy. Transcriptomic profiling indicated the combination modulated innate immune and apoptotic pathways with downregulation of TREM2, inhibition of NF-kappaB p65 activation, reduced microglial activation and cytokine expression, and a rebalanced Bcl-2/Bax ratio. TREM2 overexpression entirely reversed the neuroprotective benefit.
Side by side.
| NAD+ | SS-31 | |
|---|---|---|
| Evidence maturity | Early clinical | Approved drug |
| Studies cited here | 15 | 16 |
| Published 2023 or later | 11 | 11 |
| Newest paper | 2026 | 2026 |
| Molecular class | An endogenous redox cofactor and enzyme substrate. Because NAD+ itself is poorly absorbed orally, the human literature is almost entirely about the precursors nicotinamide riboside and nicotinamide mononucleotide rather than the cofactor as supplied. | A synthetic mitochondria-targeted tetrapeptide with no endogenous counterpart, developed as a pharmaceutical candidate. |
| Mechanism | Substrate availability for sirtuins, PARPs and CD38, which compete for one NAD+ pool. Precursor supplementation reliably raises circulating NAD+ two- to threefold in randomised trials. | Binding to cardiolipin in the inner mitochondrial membrane, stabilising cristae architecture and improving electron transport efficiency and ATP synthesis. A 2013 rat kidney ischaemia-reperfusion study established that mechanism. |
| Regulatory status | Sold as a supplement in most jurisdictions rather than approved as a drug for any indication, with precursor trials conducted under investigational protocols. | An approved drug. The FDA granted accelerated approval on 19 September 2025 to improve muscle strength in adult and paediatric Barth syndrome patients weighing at least 30 kg, based on a knee extensor strength improvement, with continued approval contingent on confirmatory trials. |
| Volume and type of human evidence | Numerous randomised double-blind placebo-controlled trials in healthy middle-aged and older adults, prediabetes, peripheral artery disease, hypertension, long COVID, mild cognitive impairment and Friedreich's ataxia, with participant numbers from 25 to 90 per trial and durations from 14 days to 24 weeks. | Randomised double-blind placebo-controlled trials in rare mitochondrial disease and heart failure, plus a single-dose study in 39 healthy older adults. The phase 3 trial in primary mitochondrial myopathy enrolled 218 participants. |
| Record on primary endpoints | Frequently null. A meta-analysis of NMN and NR found no significant effect on skeletal muscle index, handgrip strength, gait speed or the chair stand test; a 15-trial NMN meta-analysis found no effect on body weight, BMI, fasting glucose, HbA1c, lipids or systolic blood pressure; a long COVID trial found no differences in cognition, fatigue, sleep, anxiety or depression despite a 2.6- to 3.1-fold NAD+ rise. | Also frequently null. MMPOWER-3 missed its primary endpoints in 218 participants, the PROGRESS-HF trial in 71 heart failure patients did not improve left ventricular end-systolic volume, and the phase 2 Leber hereditary optic neuropathy trial did not meet its primary visual acuity endpoint. |
| Where each has shown something positive | Scattered individual trials: increased muscle insulin sensitivity in 25 prediabetic postmenopausal women, a 17.6 metre gain in six-minute walk distance in peripheral artery disease, improved walking time and sleep quality in older adults on secondary outcomes, and a peak VO2 gain in Friedreich's ataxia only when combined with exercise. | The Barth syndrome programme, where a 168-week open-label extension in a very small cohort reported a 96.1 metre cumulative six-minute walk improvement, and a randomised single-dose study showing improved in vivo skeletal muscle ATP production in 39 healthy older adults. |
| Evidence in healthy people seeking performance or ageing benefit | Present but largely negative on function. Trials in healthy middle-aged and older adults show the NAD+ rise reliably; the muscle and metabolic meta-analyses do not support the precursors for preserving muscle mass or function, and no trial has shown durable improvement in muscle mass, cognition, glycaemic control or blood pressure. | Essentially absent. Apart from the single-dose ATP production study in 39 healthy older adults, there are no controlled trials in healthy individuals for exercise capacity, athletic performance, longevity or body composition. |
And what it does not.
Direct comparative evidence exists here and it is worth reading carefully, because it does not deliver a winner. In aged mouse hearts the two agents corrected different things, SS-31 partially reversing a diastolic decline and NMN fully reversing a systolic deficiency at higher workload, with the combination producing effects neither achieved alone; in a mouse stroke model co-administration outperformed both monotherapies. All of that is rodent work using a precursor rather than NAD+ itself, in specific injury and ageing models, and none of it has been reproduced in a human. The regulatory asymmetry is real but must not be read as an efficacy verdict. Elamipretide holds an accelerated approval resting on a muscle-strength surrogate in a very small Barth syndrome cohort, with confirmatory clinical benefit not yet demonstrated, and it missed primary endpoints in its largest mitochondrial myopathy trial and in its heart failure and optic neuropathy trials. NAD+ precursors have a larger and more varied randomised literature that reliably raises circulating NAD+ two- to threefold and just as reliably fails to move the functional endpoints, with null meta-analyses for muscle, metabolic and blood pressure outcomes and a handful of scattered positive individual trials. Neither compound has controlled evidence supporting use in healthy people for performance, body composition or ageing, and for NAD+ itself, as opposed to its oral precursors, human evidence is essentially absent because the cofactor is not orally bioavailable.
Common questions.
- Has any experiment given elamipretide and an NAD+ precursor to the same animals?
Yes, at least three. Two studies from the same group treated aged mouse hearts with SS-31, nicotinamide mononucleotide, or both, examining cardiac function, metabolomics and the proteome and acetylome. A 2026 study administered SS-31, NMN or the combination to mice in a middle cerebral artery occlusion and reperfusion model. All three are rodent experiments; no human study has given both.
- What did the aged mouse heart study find for each agent separately?
SS-31 partially reversed an age-related decline in diastolic function, while nicotinamide mononucleotide fully reversed an age-related deficiency in systolic function at a higher workload. Both normalised PCr/ATP dynamics under increased workload. Only NMN raised NAD+ in response to increased work, and only the combined treatment produced significantly greater steady-state NAD(H) levels.
- Does an FDA approval mean elamipretide outperforms NAD+ precursors?
It does not, and reading it that way misstates both records. The approval is an accelerated approval for Barth syndrome, granted on a knee extensor muscle strength surrogate in a very small cohort, with continued approval contingent on confirmatory trials. The same compound missed its primary endpoints in a 218-participant phase 3 mitochondrial myopathy trial, in a 71-patient heart failure trial and in a Leber hereditary optic neuropathy trial.
- Do human NAD+ trials actually administer NAD+ itself?
Almost never. NAD+ is poorly absorbed orally, so the randomised human literature uses the precursors nicotinamide riboside and nicotinamide mononucleotide. These reliably raise circulating NAD+ two- to threefold. A 2026 study also reported that gut microbiota convert both precursors to nicotinic acid, which was the potent direct NAD+ booster in whole blood, so even the assumed route of the effect is under revision.
- Have the NAD+ precursor trials improved anything people would notice?
Inconsistently, and the pooled picture is null. Meta-analyses found no significant effect on skeletal muscle index, handgrip strength, gait speed, chair stand performance, body weight, glucose, HbA1c, lipids or systolic blood pressure. Individual trials reported a 17.6 metre six-minute walk gain in peripheral artery disease, improved muscle insulin sensitivity in 25 prediabetic women, and better sleep quality in older adults on secondary outcomes, against a long COVID trial that found no differences in cognition, fatigue or sleep despite a clear NAD+ rise.
- Is there controlled evidence for either compound in healthy adults seeking performance gains?
Barely, and what exists does not support that use. For elamipretide the only healthy-population data are a randomised single-dose study in 39 healthy older adults measuring skeletal muscle ATP production by magnetic resonance spectroscopy, a bioenergetic rather than performance endpoint. NAD+ precursor trials in healthy middle-aged and older adults reliably raise blood NAD+, but the muscle-function meta-analysis concluded the evidence does not support them for preserving muscle mass or function.
For research purposes only. Not for human consumption, diagnosis, treatment, or prevention of any condition. Nothing on this page is medical advice, and no comparison here should be read as a recommendation of either compound.