Hi…sorry it has taken me so long to respond. Your question addresses one of the many things about rapamycin that have not been adequately tested in humans. I regularly combine intermittent fasting with rapamycin. IN Blagosklonny’s 2019 article titled Fasting and rapamycin: diabetes versus benevolent glucose intolerance…he states " asting and rapamycin: diabetes versus benevolent glucose intolerance."
2 Likes
4x a year I fast for 96 hours, just electrolytes and water intake. I found an interesting report that adequate intake of spermidine may be required to achieve highest levels of autophagy under those conditions.
1 Like
Here is a summary of that paper you linked to, interesting reading:
Spermidine is essential for fasting-mediated autophagy and longevity
Fasting and caloric restriction extend lifespan, and this study shows why: fasting drives cells to make more of the natural polyamine spermidine, which is then required to switch on autophagy (cellular self-cleaning) and deliver the longevity, heart-protective and anti-inflammatory benefits. Block spermidine production, and most of fasting’s benefits vanish.
For decades, researchers have known two separate facts about living longer. First, eating less, whether through continuous caloric restriction or intermittent fasting, reliably extends the healthy lifespan of organisms from yeast to mice. Second, a humble molecule called spermidine, found in foods like wheat germ, aged cheese and soybeans, does something remarkably similar when supplemented. What nobody had nailed down was whether these two stories were actually one story.
This international team has now connected them. Working across an unusually broad sweep of biology, yeast, fruit flies, nematode worms, mice and human volunteers, they show that fasting itself raises spermidine levels inside cells. When they measured polyamines by mass spectrometry, the pattern was consistent everywhere: starve the organism, and spermidine climbs. In human volunteers undergoing supervised therapeutic fasting, blood spermidine rose by roughly half within four to five days.
The crucial experiments were the knockouts. Using genetic deletions and a drug called DFMO that blocks the rate-limiting enzyme (ODC1) in spermidine synthesis, the researchers asked what happens when fasting can no longer raise spermidine. The answer was striking. In yeast, worms and flies, blocking spermidine abolished fasting’s lifespan extension. In aged mice, blocking it erased fasting’s protection of the aging heart and its preservation of muscle strength. In a mouse model of inflammatory arthritis, it wiped out fasting’s anti-inflammatory benefit. Fasting, in other words, mostly stops working without spermidine.
The mechanism runs deeper still. Spermidine is the sole chemical donor for a reaction called hypusination, a unique modification of a single protein, the translation factor eIF5A. Hypusinated eIF5A is needed to produce the autophagy machinery. The team traced the full chain, fasting raises spermidine, spermidine hypusinates eIF5A, hypusinated eIF5A enables autophagy, and autophagy delivers the longevity benefit, and showed that breaking any link breaks the outcome.
The big idea is that the spermidine–hypusination axis is a conserved control hub, a common bottleneck through which fasting’s diverse benefits must pass. This reframes spermidine not as merely a fasting-mimetic supplement, but as an obligatory downstream effector of fasting biology itself. [Confidence: High for the conserved requirement; Medium for the precise human relevance.]
Actionable Insights
The most defensible take-home is mechanistic rather than prescriptive: fasting and spermidine are not competing strategies but the same pathway. This study does not test whether oral spermidine substitutes for fasting in humans, but it strengthens the rationale for ensuring adequate spermidine.
Effect sizes worth knowing. In human volunteers, supervised fasting raised serum spermidine by approximately 50% after 4–5 days (cohort 2), an increase sustained through long-term fasting. This is the real-world magnitude of the “fasting raises spermidine” claim, and it is substantial. In aged mice, the downstream consequences of preserving this pathway were large: intermittent-fasting-plus-CR improvements in grip strength were highly significant (P = 9.8 × 10⁻⁶ for the fasting effect), and cardiac diastolic function (E/e′) and left-ventricular mass each improved significantly with fasting (P ≈ 0.042–0.043) but only when spermidine synthesis was intact.
Practically, this supports two low-risk levers already grounded in prior human data: (1) intermittent fasting or caloric restriction regimens, which this paper shows act partly through endogenous spermidine; and (2) dietary spermidine intake, which a prior prospective cohort (Kiechl et al., 2018) linked to lower all-cause mortality. The honest caveat: causal benefit of supplementation in humans is not demonstrated here. [Confidence: Medium.]
Context
- Lead institutions: University of Graz (Austria); Institute of Molecular Biology and Biotechnology, FORTH, and University of Crete (Greece); Centre de Recherche des Cordeliers / Institut Gustave Roussy / Hôpital Européen Georges Pompidou (Paris, France). The study is a large multicentre consortium also including the Medical University of Graz, University of Maribor (Slovenia), and the U.S. National Institute on Aging (NIH, Baltimore).
- Countries: Austria, Greece, France (lead), with Slovenia and USA contributing.
- Corresponding authors: Nektarios Tavernarakis, Guido Kroemer, Frank Madeo.
- Journal: Nature Cell Biology (Nature Portfolio).
- Impact Evaluation The impact score of this journal is approximately 19.5 (2024 Journal Impact Factor; CiteScore approximately 40.2), evaluated against a typical high-end range of 0–60+ for top general-science and flagship subject journals, therefore this is an Elite impact journal. Nature Cell Biology is a Q1 flagship in cell biology and one of the highest-impact specialist journals in the life sciences.
Novelty — What We Didn’t Know Yesterday
- Fasting and caloric restriction causally require endogenous spermidine synthesis to extend lifespan/healthspan, rather than merely correlating with it. Prior work showed spermidine supplementation mimics fasting; this shows fasting depends on spermidine.
- The dependency operates specifically through eIF5A hypusination, identifying a single post-translational modification as a conserved bottleneck for fasting’s benefits.
- The requirement is phylogenetically conserved across yeast, worms, flies and mice, and the spermidine rise is documented in fasting humans, unifying two previously parallel longevity literatures (dietary restriction and polyamines).
Critical Limitations (told straight)
- No mouse lifespan data. Mammalian claims are healthspan only. The title’s word “longevity” is carried by invertebrates and yeast, not mice. Do not over-read mammalian survival benefit.
- No human intervention on outcomes. Human data are biomarker associations (spermidine and eIF5A^H rise during fasting). There is no human endpoint showing that blocking or boosting spermidine changes a health outcome. Translational uncertainty is high.
- Small mammalian N with no confidence intervals. Cardiac arms as low as n = 8–9; effect sizes reported as means ± s.e.m. with p-values only. Wide uncertainty, real risk of effect-size inflation in significant interaction terms. Several outcomes hinge on DFMO × IF interaction p-values near 0.04, which are fragile.
- DFMO is not a clean tool. DFMO/ODC1 inhibition has pleiotropic effects beyond spermidine (e.g., putrescine, ornithine pools, possible off-target metabolic and antiproliferative actions). Attributing the whole phenotype to spermidine specifically rests partly on rescue experiments, which are stronger in yeast/worms than in mice.
- Statistical inconsistency across species. Heavy reliance on p-values; multiple-comparison handling varies (ANOVA with Holm-Šídák, FDR, log-rank with Bonferroni). Some “trends” (P = 0.140, 0.222, 0.072) are interpreted favorably.
- Mechanistic gap acknowledged by authors. They state the biochemical mechanism by which fasting/CR stimulates polyamine synthesis “remains elusive, limiting the novelty,” and that isocaloric IF studies in rodents/humans give mixed outcomes. The IF-vs-CR contribution to spermidine is unresolved.
- Cancer caveat. Authors note elevated polyamines occur in many cancers and can drive proliferation; the IF/spermidine strategy in cancer patients is explicitly unevaluated. This is a safety-relevant limitation for biohackers stacking spermidine. [Confidence: High that caution is warranted.]
1 Like