What the Cell Is Actually Doing

A closer look at NAD⁺, mitochondrial recycling and cellular senescence.

There is a moment on a hiking trail when a familiar incline feels harder than you remember. Your legs ask for a pause. It is tempting to read that moment as a message from aging cells. But a slower climb cannot tell you what is happening inside your mitochondria, or whether you need a supplement.

That distinction matters when we talk about longevity. Researchers can measure a change inside a cell without demonstrating a change in how someone feels or functions. Understanding the difference makes the science more interesting—and the claims around it easier to judge.

Here is a closer look at several processes behind the conversation, with particular attention to what the studies actually measured. This is a discussion of research, not evidence that any RESETTA product reproduces these findings.

NAD⁺ and Cellular Energy

NAD⁺, short for nicotinamide adenine dinucleotide, participates in reactions that help cells obtain energy from nutrients. It also supports enzymes involved in DNA repair. Researchers study how NAD⁺ metabolism changes with age, but it is too simple to assume that everyone develops the same deficiency or that restoring a blood measurement will restore youthful function. [1, 2]

NR, or nicotinamide riboside, and NMN, or nicotinamide mononucleotide, are precursors used in NAD⁺ synthesis. In a 2016 mouse study, NR affected mitochondrial and stem-cell function and increased lifespan — findings in mice, not evidence that NR extends human life. [3]

The human evidence is more measured. A systematic review published in 2026 identified 113 intervention studies, including 33 in humans. Oral NR and NMN generally increased measured NAD-related metabolites, while effects on physical function, metabolism and other health-related outcomes varied and were frequently absent or limited to particular measurements. [1]

A higher NAD-related blood measurement tells researchers that an intervention reached a biological target. Whether someone will feel less tired, climb more easily or live longer is a separate question. The review did not establish those benefits as reliable outcomes. [1]

Mitophagy and Mitochondrial Recycling

Mitochondria help produce the ATP that powers many cellular activities. Cells also maintain these structures, including through mitophagy, a process that removes damaged mitochondria. Urolithin A is studied in relation to that process. Gut microbes can produce it from compounds found in foods such as pomegranates and walnuts, although production varies between people. [4]

A 2022 trial assigned 88 adults aged 40–64 to urolithin A or placebo for four months. Some hamstring strength measures improved relative to placebo, but the primary outcome, peak power output, did not. The often-quoted 12% figure concerned a specific strength measure in one dose group, not overall strength or everyday stamina. [4]

A separate trial, published in Nature Aging in 2025, studied 50 adults for four weeks and reported changes in certain immune-cell populations and metabolic measures. It did not establish fewer infections, longer life or clinically reversed immune aging. [5, 6]

Senescence and the Limits of the Cleanup Metaphor

Cellular senescence is a state in which cells stop dividing but remain metabolically active. Some senescent cells release signals that affect surrounding tissue. Senescence also has useful biological roles, including limiting the replication of damaged cells, so describing every senescent cell as waste to be removed misses part of the picture. [7]

Senolytics are studied for their ability to selectively eliminate certain senescent cells. Fisetin, a plant flavonoid, showed activity in laboratory experiments and mice in a 2018 study. The screen of ten flavonoids was a laboratory comparison — not a trial showing fisetin was the best supplement for people. [7]

A 2025 mouse study reported better grip strength and frailty measures in older animals, with no corresponding effects in young mice, and no increase in skeletal muscle mass. These results support further investigation; they do not demonstrate that fisetin supplements preserve human muscle or extend human life. [8]

Spermidine and Autophagy

Spermidine belongs in a related but distinct conversation. It is a naturally occurring polyamine investigated for effects on autophagy, the broader process through which cells recycle internal components. Autophagy is not the same as eliminating whole senescent cells. [9]

A prospective study linked higher dietary spermidine intake with lower mortality. Because participants were observed rather than randomly assigned to a supplement, the study cannot establish that spermidine caused the difference or that a capsule would reproduce it. [10]

In the 2022 SmartAge trial, 100 older adults with subjective cognitive decline were assigned to a spermidine-rich extract or placebo for 12 months. The intervention did not significantly improve the primary memory outcome. Adverse events were balanced between groups. [11]

How to Read a Longevity Claim

The mechanisms are worth understanding. They are not a shopping list. Before drawing a conclusion from a study, ask: Was the intervention tested in people, animals or cells in a laboratory? Did it change a biomarker, a meaningful measure of function or a long-term health outcome? Did it meet its prespecified primary outcome, against the control group? Does the product match the studied formulation, dose and population — and has the result been independently repeated?

The answers usually require looking beyond the label. Even a randomized human trial answers a specific question under specific conditions; it does not settle every claim attached to an ingredient.

Back on the trail, the harder incline remains a personal experience, not a diagnosis of a cellular problem. We can be curious about what our cells are doing without assuming that a supplement is the missing piece. That is the kind of curiosity worth keeping: interested in the possibility, attentive to the evidence.

References

1. Gallagher C, Emmanuel OO. NAD⁺ supplementation for anti-aging and wellness. Ageing Research Reviews. 2026;116:103057.
2. Martens CR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD⁺ in healthy middle-aged and older adults. Nature Communications. 2018;9:1286. doi.org/10.1038/s41467-018-03421-7
3. Zhang H, et al. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436–1443. doi.org/10.1126/science.aaf2693
4. Singh A, et al. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Reports Medicine. 2022;3(5):100633. PMC
5. Denk D, et al. Effect of the mitophagy inducer urolithin A on age-related immune decline. Nature Aging. 2025;5:2309–2322. doi.org/10.1038/s43587-025-00996-x
6. Denk D, et al. Author Correction. Nature Aging. 2026.
7. Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18–28. doi.org/10.1016/j.ebiom.2018.09.015
8. Murray KO, et al. Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging. Aging Cell. 2025;24(8):e70114. doi.org/10.1111/acel.70114
9. Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018;359(6374):eaan2788. doi.org/10.1126/science.aan2788
10. Kiechl S, et al. Higher spermidine intake is linked to lower mortality. American Journal of Clinical Nutrition. 2018;108(2):371–380. doi.org/10.1093/ajcn/nqy102
11. Schwarz C, et al. Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline. JAMA Network Open. 2022;5(5):e2213875. doi.org/10.1001/jamanetworkopen.2022.13875