Autophagy & Mitophagy (Spermidine, Urolithin A) — References

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• Parent Topic: Autophagy & Mitophagy (Spermidine, Urolithin A)
• Reference Hub: 04 - Longevity & Environment References MOC

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Primary Literature Dossier

1. Andreux et al. (2019) — First-in-Human Urolithin A Trial Induces Mitochondrial Biogenesis and Mitophagy Signatures

• Citation: Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, Auwerx J, Singh A, Rinsch C. The mitophagy activator urolithin A is safe and induces a molecular signature of mitochondrial biogenesis and cellular health in humans. Nature Metabolism. 2019 Jun;1(6):595-603.
• Identifiers: PMID: 32694802 (PubMed · Europe PMC) | DOI: 10.1038/s42255-019-0073-4 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Phase 1, randomized, double-blind, placebo-controlled ascending-dose clinical trial ($n=60$ healthy, sedentary elderly subjects; single doses $250\text{–}2,000\text{ mg}$ and 28-day chronic dosing at $250,500,$ and $1,000\text{ mg/day}$ with vastus lateralis skeletal muscle biopsies).
• Key Quantitative Outcomes:
  • Oral Urolithin A was bioavailable across all subjects ($t_{1/2}\approx 17\text{–}22\text{ h}$ for parent UA and UA-glucuronide/sulfate), overcoming gut microbiome non-producer variance.
  • At $500\text{ mg}$ and $1,000\text{ mg/day}$ for 28 days, plasma acylcarnitines ($\text{C8, C10, C12, C14:1}$) decreased by 20–35% ($p<0.05$), indicating enhanced mitochondrial fatty acid oxidation.
  • Skeletal muscle RNA-seq and qPCR confirmed dose-dependent upregulation of mitochondrial respiratory complexes and autophagy/mitophagy transcripts ($\text{GABARAPL1, FABP3}$), mimicking the transcriptomic profile of regular aerobic exercise.

2. Liu et al. (2022) — Urolithin A Improves Muscle Endurance and Mitochondrial Biomarkers in Older Adults

• Citation: Liu S, D’Amico D, Shankland E, Bhayana S, Garcia JM, Aebischer P, Rinsch C, Singh A, Marcinek DJ. Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial. JAMA Network Open. 2022 Jan 4;5(1):e2144279.
• Identifiers: PMID: 35048098 (PubMed · Europe PMC) | DOI: 10.1001/jamanetworkopen.2021.44279 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Randomized, double-blind, placebo-controlled trial ($n=66$ older adults aged 65–90 years; $1,000\text{ mg/day}$ Urolithin A vs. placebo for 4 months).
• Key Quantitative Outcomes:
  • At 2 months, resistance to fatigue (number of muscle contractions until exhaustion) increased significantly in the UA group vs. placebo in both skeletal hand muscle (first dorsal interosseous: $+95.3$ vs. $+11.6$ contractions, $p=0.02$) and leg muscle (tibialis anterior: $+41.4$ vs. $+5.7$ contractions, $p=0.03$).
  • At 4 months, plasma acylcarnitines, ceramides, and C-reactive protein (CRP) decreased significantly in the Urolithin A arm ($p<0.05$) compared to placebo.

3. Singh et al. (2022) — Urolithin A Enhances Muscle Strength, Exercise Performance, and Mitophagy Proteins in Middle-Aged Adults

• Citation: Singh A, D’Amico D, Andreux PA, Fouassier AM, Blanco-Bose W, Evans M, Aebischer P, Auwerx J, Rinsch C. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Reports Medicine. 2022 May 17;3(5):100633.
• Identifiers: PMID: 35584623 (PubMed · Europe PMC) | DOI: 10.1016/j.xcrm.2022.100633 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Randomized, double-blind, placebo-controlled trial ($n=88$ overweight, sedentary middle-aged adults aged 40–64 years; placebo, $500\text{ mg/day}$, or $1,000\text{ mg/day}$ Urolithin A for 4 months, with skeletal muscle proteomic biopsies).
• Key Quantitative Outcomes:
  • Hamstring skeletal muscle strength increased significantly in both the $500\text{ mg}$ ($+12.0\%$, $p=0.027$) and $1,000\text{ mg}$ ($+9.8\%$, $p=0.029$) groups vs. placebo.
  • In the $1,000\text{ mg}$ group, peak aerobic capacity (${\text{VO}}_2\text{ peak}$) increased by $+10.2\%$ ($p<0.01$), peak cycling power output rose by $+8.3\%$, and 6-minute walk distance improved by $+33\text{ m}$.
  • Muscle proteomics confirmed increased phosphorylation of Parkin at Ser65 (direct biochemical marker of PINK1/Parkin mitophagy) and elevated OXPHOS Complex I, II, and III protein abundance.

4. Kiechl et al. (2018) — Higher Spermidine Intake Is Linked to Lower Mortality in Humans

• Citation: Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, Werner P, Della Valle C, Willeit J, Mayr M, Kronenberg F, Eisenberg T, Madeo F. Higher spermidine intake is linked to lower mortality: a prospective population-based study. The American Journal of Clinical Nutrition. 2018 Aug 1;108(2):371-380.
• Identifiers: PMID: 29955838 (PubMed · Europe PMC) | DOI: 10.1093/ajcn/nqy102 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Prospective population-based cohort study (Bruneck Study, $n=829$ adults aged 45–84 years followed over 20 years with repeated validated food-frequency polyamine assessments; findings replicated in the SAPHIR cohort).
• Key Quantitative Outcomes:
  • All-cause mortality decreased steadily across increasing tertiles of dietary spermidine intake from 40.5 deaths per 1,000 person-years (lowest tertile, $<9\text{ mg/day}$) to 24.0 (middle) and 15.1 (highest tertile, $>11.6\text{ mg/day}$).
  • Multivariable-adjusted hazard ratio for all-cause mortality comparing top vs. bottom tertile of spermidine intake was $\text{HR }0.60$ ($95\%\text{ CI}:0.50\text{–}0.74,p<0.001$), equivalent to a 5.7-year reduction in biological mortality risk, driven by lower fatal heart failure, vascular, and cancer events.