For decades, aging research has focused purely on lifespan - how long we live. Increasingly, however, scientists are asking a more meaningful question: how well do we live as we age? A new clinical study now underway in the U.S. is testing whether a targeted combination of spermidine, exercise and anti-inflammatory medicines can increase healthspan along with lifespan.
The study is enrolling healthy adults aged 65- 80 and brings together three interventions that, individually, have shown promise in aging research:
- High-intensity interval training (HIIT) combined with resistance exercise.
- The dietary supplement, spermidine (as found in Primeadine).
- Low-dose anti-inflammatory medications.
Inflammaging
One of the central ideas behind this research is the concept of inflammaging [1]. As we grow older, the immune system can become dysregulated, meaning instead of short, targeted inflammatory responses to injury or infection, inflammation can remain persistently activated, producing low-grade, chronic inflammation throughout the body.
This chronic inflammation is not benign, it can underlie many diseases that become more common with age. In the framework of the “hallmarks of aging,” inflammaging intersects with several core processes: immune dysfunction, mitochondrial decline, cellular senescence, and altered intercellular communication [2].
The researchers behind this study hypothesize that reducing harmful inflammation, while preserving the immune system’s ability to respond appropriately, could slow the biological processes that drive age-related decline.
Step 1: Exercise
Exercise, particularly when it includes both cardiovascular and strength-based components, is one of the most robust interventions known to promote healthy aging [3]. In this study, participants perform short daily sessions of HIIT interspersed with resistance training using bands or bodyweight exercises. Regular physical activity is known to improve many aspects of health and, crucially for this study, exerts anti-inflammatory effects through modulation of immune signaling, decreasing visceral fat (a major source of inflammatory cytokines), and improving mitochondrial function, addressing several hallmarks of aging simultaneously.
Step 2: Spermidine
A distinctive feature of the study is the inclusion of spermidine, the naturally occurring polyamine you recognize from Primeadine. Spermidine has attracted attention in aging research because of its ability to stimulate autophagy - the process by which cells recycle damaged components and maintain internal quality control [4].
Autophagy declines with age, leading to the accumulation of dysfunctional proteins and organelles that contribute to cellular stress and inflammation. By enhancing autophagy, spermidine may help restore cellular homeostasis and dampen inflammatory signaling [5].
Importantly, spermidine also appears to influence immune function directly. Both pre-clinical and observational studies suggest it can reduce the production of pro-inflammatory cytokines while supporting immune balance [6]. Lower levels of spermidine have been observed with advancing age, and supplementation has been associated with reduced mortality in population studies [7]. Considering these prior studies, this trial represents a critical step toward testing spermidine’s effects in a controlled, specific, interventional setting.
Step 3: Inflammation with Repurposed Medicines
In addition to exercise and supplementation, participants receive one of two long-approved medications - lamivudine or rapamycin - at carefully selected doses. Both drugs have known anti-inflammatory properties and act on immune pathways implicated in aging biology [8,9].
Rapamycin, in particular, has become a focal point in longevity research because it modulates the mTOR pathway (similar to fasting), a key regulator of growth, metabolism, and aging. Whether similar benefits can be achieved safely in healthy older adults remains an open question, one this study is designed to explore.
Measuring Aging at the Molecular Level
Rather than relying solely on physical outcomes, the researchers are conducting deep molecular analyses throughout the year-long study. Blood samples will be examined using high-resolution proteomics, measuring thousands of immune signaling proteins to build a detailed picture of inflammatory and immune changes over time. By mapping these shifts, the team hopes to identify biomarkers of “bad” inflammation and determine whether this combined intervention meaningfully reverses age-associated immune dysfunction.
A Shift Toward Healthspan
This study reflects a shift in aging research toward evidence-based strategies that support healthspan rather than chase single-pathway cures. Spermidine emerges as a promising nutritional intervention, particularly when combined with lifestyle factors such as regular exercise, together targeting multiple hallmarks of aging. While early-stage, the findings support an integrated approach to aging - one aimed not at extending lifespan alone, but at preserving mobility, independence, and cognitive health for longer.
References
[1] Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018 Sep;15(9):505-522. doi: 10.1038/s41569-018-0064-2. PMID: 30065258; PMCID: PMC6146930
[2] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349.
[3] Izquierdo M, Fiatarone Singh MA. Evidence-based exercise enhances healthy aging. J Nutr Health Aging. 2025 Jan;29(1):100411. doi: 10.1016/j.jnha.2024.100411. Epub 2024 Dec 31. PMID: 39746235; PMCID: PMC12180035
[4] Ni YQ, Liu YS. New Insights into the Roles and Mechanisms of Spermidine in Aging and Age-Related Diseases. Aging Dis. 2021 Dec 1;12(8):1948-1963. doi: 10.14336/AD.2021.0603. PMID: 34881079; PMCID: PMC8612618
[5] Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018 Jan 26;359(6374):eaan2788. doi: 10.1126/science.aan2788. PMID: 29371440.
[6] Zhang M, Caragine T, Wang H, Cohen PS, Botchkina G, Soda K, Bianchi M, Ulrich P, Cerami A, Sherry B, Tracey KJ. Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: a counterregulatory mechanism that restrains the immune response. J Exp Med. 1997 May 19;185(10):1759-68. doi: 10.1084/jem.185.10.1759. PMID: 9151701; PMCID: PMC2196317
[7] Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, Werner P, Ruckenstuhl C, Iglseder B, Weger S, Mairhofer B, Gartner M, Kedenko L, Chmelikova M, Stekovic S, Stuppner H, Oberhollenzer F, Kroemer G, Mayr M, Eisenberg T, Tilg H, Madeo F, Willeit J. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018 Aug 1;108(2):371-380. doi: 10.1093/ajcn/nqy102. PMID: 29955838.
[8] Roark KM, Iffland PH 2nd. Rapamycin for longevity: the pros, the cons, and future perspectives. Front Aging. 2025 Jun 20;6:1628187. doi: 10.3389/fragi.2025.1628187. PMID: 40620657; PMCID: PMC12226543
[9] Chen X, Wang H, Liu Y, Zhang W, Song Z. Anti-inflammatory effect of lamivudine on ulcerative colitis. Biochem Biophys Rep. 2025 Oct 22;44:102317. doi: 10.1016/j.bbrep.2025.102317. PMID: 41189640; PMCID: PMC12581620



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