The PEARL trial (NCT04488601) enrolled 114 adults aged 50 to 85 and randomized participants to 5 mg rapamycin weekly, 10 mg rapamycin weekly, or placebo for 48 weeks [1]. The primary endpoint, visceral adiposity, was not significantly changed (p = 0.942). Secondary findings were more informative: lean tissue mass improved in women receiving 10 mg at 24 and 48 weeks (p = 0.013), pain scores declined with the same dose (p = 0.015), and general health ratings improved in the 5 mg group (p = 0.004). Gastrointestinal adverse events were modestly higher in rapamycin arms, with serious adverse event counts similar across groups [1].

The urolithin A trial published in Nature Aging (NCT05735886) tested Mitopure at 1,000 mg per day versus placebo in 50 healthy adults aged 45 to 70 for four weeks [10]. Urolithin A, a postbiotic produced from ellagitannin metabolism, promotes selective mitophagy. The trial found significant increases in naive-like CD8+ T cells (+0.50 percentage points, p = 0.0437) and CD8+ fatty acid oxidation capacity (+14.72 percentage points, p = 0.0061). Single-cell RNA sequencing confirmed transcriptional shifts consistent with reduced immune exhaustion across multiple cell populations, positioning urolithin A as one of the better-characterized immune-longevity compounds in the current evidence base [10].

2. NAD+ Precursors Under Scrutiny: NMN and NR

Two 2025 analyses recalibrated expectations for the NAD+ precursor category, which has attracted considerable commercial attention: a meta-analysis of NMN across 12 RCTs and a crossover RCT of nicotinamide riboside (NR) in adults with mild cognitive impairment.

Zhang et al.'s 2025 meta-analysis (12 RCTs, N = 513) found that blood NAD+ levels were significantly elevated by oral NMN across all trials [2]. Clinical metabolic endpoints, including fasting glucose, HbA1c, and lipids, were not significantly different from placebo in the aggregate. The analysis identified 600 mg per day as the dose with the clearest metabolic signal, though that signal did not reach significance in the pooled data. Seven studies carried "some concerns" and five "high risk of bias" on risk-of-bias assessment, limiting confidence in the pooled estimates [2].

The NR crossover trial by Wu et al. enrolled 46 adults older than 55 with subjective cognitive decline or mild cognitive impairment (MCI) [3]. NR did not significantly improve performance on primary cognitive assessments. However, it produced a statistically significant reduction in plasma pTau217, an Alzheimer's biomarker reflecting tau phosphorylation (p = 0.02 versus placebo), and step count increased significantly during the NR phase (p = 0.04). The trial was well tolerated, with no between-group differences in adverse events [3]. Both analyses confirm that NAD+ elevation is measurable and consistent; which downstream clinical outcomes that elevation actually improves requires longer, more targeted trial designs.

3. Senolytics: Clearing Senescent Cells

Two 2024–2025 senolytic studies contributed distinct types of evidence: one opened a new patient population for investigation, the other raised a calibration question about the measurement tools the field is relying on.

The protocol by Schweiger et al. (NCT05838560) formalizes the first senolytic trial in serious mental illness, targeting adults aged 50 or older with schizophrenia and adults aged 60 or older with treatment-resistant depression (N = 30 planned) [4]. The regimen is 100 mg dasatinib plus 1,250 mg quercetin for two consecutive days at baseline and weeks 1 to 3, with assessments at baseline, week 10, and one year. Results are expected in 2025–2026 and will constitute the first human data on whether senolytics can alter mental illness trajectories in older adults [4].

The Lee et al. longitudinal pilot tested dasatinib plus quercetin (DQ) or a triple combination adding fisetin 500 mg (DQF) over six months in 19 participants per phase [5]. The first-generation PC Horvath clock showed a significant increase at three months in the DQ arm (p = 6.7 × 10⁻⁶), with partial reversal at six months. DNAm telomere length decreased significantly (p = 4.4 × 10⁻⁴). Second and third-generation clocks showed no significant changes [5]. This divergence across clock generations indicates that no single epigenetic clock should serve as a definitive senolytic trial endpoint without pre-specified justification for the generation selected.

4. The Gut-Metabolic Axis: Akkermansia, GLP-1, and Berberine

Four 2025 papers on the gut-metabolic interface collectively established that individual baseline microbiota composition is a key determinant of probiotic response, and that berberine now has one of the strongest aggregate evidence bases of any botanical metabolic compound.

A double-blind RCT in Cell Metabolism (N = 58, 12 weeks, type 2 diabetes) found that A. muciniphila (AKK-WST01) supplementation produced significant reductions in body weight, fat mass, and HbA1c only in participants with low baseline abundance; those with high baseline levels showed poor colonization and no benefit [6]. A systematic review by Gofron et al. covering 38 studies found that GLP-1 agonists consistently increase A. muciniphila but semaglutide simultaneously decreases overall gut diversity [7]. Individuals already on GLP-1 therapy may therefore be experiencing a pharmacologically driven Akkermansia increase, which contextualizes whether additional supplementation is additive.

For berberine, a phase 2 RCT in JAMA Network Open (N = 113, 12 weeks) tested HTD1801, a berberine-ursodeoxycholic acid conjugate [8]. The 1,000 mg twice-daily dose reduced HbA1c by 0.7 percentage points (p < 0.001) and fasting plasma glucose by 18.4 mg/dL; completion rate was 97.3% [8]. A meta-analysis by Liu et al. confirmed berberine's effects across multiple RCTs: triglycerides WMD −0.367 mmol/L (p < 0.001), fasting plasma glucose WMD −0.515 mmol/L (p = 0.002), and waist circumference WMD −3.270 cm (p < 0.001); HDL and blood pressure were not significantly changed [9].

5. Cognitive Longevity: Lion's Mane and Phosphatidylserine

Two 2025 publications contributed to the evidence base for cognitive supplement research, both targeting adults with established or emerging cognitive vulnerability and both demonstrating statistically significant effects that are modest in absolute terms.

A PRISMA systematic review by Menon et al. in Frontiers in Nutrition evaluated five RCTs and 15 laboratory studies on Hericium erinaceus (lion's mane) [11]. The combined weighted mean MMSE improvement across the RCTs was 1.17 points in supplemented versus control groups. Side effects including stomach discomfort, headache, and rare allergic reactions were noted in a minority of participants; no serious adverse events were documented [11].

The phosphatidylserine complex trial by Duan et al. enrolled 190 adults with MCI (mean age 67.95) in a 12-month double-blind RCT testing PS (31.5 mg) plus ALA (144 mg) and ginkgo flavonoids versus placebo [12]. Arithmetic (β = 0.688), similarity (β = 1.070), and short-term memory (β = 0.600) scores all improved significantly versus placebo, with serum ALA levels mediating 19.7% of the memory benefit. No adverse events were recorded in either group [12].

Frequently Asked Questions

Which of these trials has the strongest evidence for a clinical effect?

By standard evidence-grading criteria, the berberine meta-analysis by Liu et al. [9] and the HTD1801 phase 2 RCT published in JAMA Network Open [8] represent the strongest combined evidence, with multiple RCTs, consistent effect sizes, and a 97.3% trial completion rate. The phosphatidylserine complex RCT [12] and the urolithin A immune trial [10] are methodologically strong within their respective outcome domains.

Is low-dose rapamycin safe for longevity use?

The PEARL trial found that 5–10 mg of compounded rapamycin taken weekly for 48 weeks was tolerable in adults aged 50 to 85, with modest increases in gastrointestinal events and no significant increase in serious adverse events versus placebo [1]. Rapamycin is a prescription-only compound in most jurisdictions and carries known interactions with CYP3A4-metabolized drugs and live vaccines; individual medical assessment is necessary before use.

Do NAD+ precursors improve cognition?

Current RCT data do not support significant improvement in standard cognitive test scores from NMN or NR supplementation in adults without severe NAD+ deficiency [2]. The NR crossover trial by Wu et al. found no significant primary cognitive improvement but did show a significant reduction in pTau217, an Alzheimer's biomarker (p = 0.02) [3]. Whether that biomarker change translates to clinical cognitive benefit over longer follow-up periods has not yet been established.

What does the Akkermansia precision finding mean in practice?

The Zhang Y et al. Cell Metabolism trial established that A. muciniphila supplementation produces significant metabolic benefits only in participants with low baseline abundance; those with high baseline levels showed neither effective colonization nor metabolic benefit [6]. This finding suggests that unselected Akkermansia supplementation would dilute any pooled effect size and that baseline microbiota profiling has a coherent mechanistic rationale as a prerequisite for probiotic selection.

How reliable are epigenetic clocks as longevity trial endpoints?

The Lee et al. senolytic pilot found that first-generation and second or third-generation DNA methylation clocks produced discordant results in the same participants at the same time points [5]. This divergence indicates that no single clock should serve as a sole primary endpoint in longevity supplement trials, and pre-specification of which clock generation is being validated has become an important trial design requirement.

References

[1] Moel M et al. "Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results." Aging (Albany NY), 2025. DOI: 10.18632/aging.206235. PMID: 40188830.

[2] Zhang J, Poon ETC, Wong SHS. "Efficacy of oral nicotinamide mononucleotide supplementation on glucose and lipid metabolism for adults: a systematic review with meta-analysis on randomized controlled trials." Critical Reviews in Food Science and Nutrition, 2025. DOI: 10.1080/10408398.2024.2387324. PMID: 39116016.

[3] Wu C-Y et al. "Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment." Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2025. DOI: 10.1002/trc2.70023. PMID: 39817194.

[4] Schweiger A et al. "Protocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders." F1000Research, 2025. DOI: 10.12688/f1000research.151963.2. PMID: 40443429.

[5] Lee E et al. "Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions." Aging (Albany NY), 2024. DOI: 10.18632/aging.205581.

[6] Zhang Y et al. "Akkermansia muciniphila supplementation in patients with overweight/obese type 2 diabetes: Efficacy depends on its baseline levels in the gut." Cell Metabolism, 2025. DOI: 10.1016/j.cmet.2024.12.010. PMID: 39879980.

[7] Gofron KK et al. "Effects of GLP-1 Analogues and Agonists on the Gut Microbiota: A Systematic Review." Nutrients, 2025. DOI: 10.3390/nu17081303. PMID: 40284168.

[8] Ji L et al. "Berberine Ursodeoxycholate for the Treatment of Type 2 Diabetes: A Randomized Clinical Trial." JAMA Network Open, 2025. DOI: 10.1001/jamanetworkopen.2024.62185. PMID: 40029660.

[9] Liu D et al. "Efficacy and safety of berberine on the components of metabolic syndrome: a systematic review and meta-analysis of randomized placebo-controlled trials." Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1572197. PMID: 40740996.

[10] Denk D et al. "Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial." Nature Aging, 2025. DOI: 10.1038/s43587-025-00996-x. PMID: 41174221.

[11] Menon A et al. "Benefits, side effects, and uses of Hericium erinaceus as a supplement: a systematic review." Frontiers in Nutrition, 2025. DOI: 10.3389/fnut.2025.1641246. PMID: 40959699.

[12] Duan H et al. "Effects of a food supplement containing phosphatidylserine on cognitive function in Chinese older adults with mild cognitive impairment: A randomized double-blind, placebo-controlled trial." Journal of Affective Disorders, 2025. DOI: 10.1016/j.jad.2024.09.131. PMID: 39317299.

This content is for informational purposes only and is not intended as medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider before starting any supplement or making changes to your health regimen.