The longevity space is full of bold claims, but occasionally a study comes along with results that are hard to ignore. One such study identified a combination of three supplements that reversed participants’ biological age by approximately two years as measured by epigenetic clocks — the most accurate biomarker of biological aging we currently have.
The TRIIM Trial
The study that generated these results was the TRIIM (Thymus Regeneration, Immunorestoration, and Insulin Mitigation) trial, which used a combination of growth hormone, DHEA, and metformin. The rationale was that growth hormone could regenerate the thymus gland (which atrophies with age and is critical for immune function), while DHEA provided hormonal support and metformin offset the insulin resistance caused by GH.
The results showed not only thymus regeneration but a measurable reversal in biological age as measured by the Horvath epigenetic clock. Participants were on average 2.5 years biologically younger at the end of the trial than at the beginning — and this was after only one year of treatment.
What This Means for the Natty Plus Community
The TRIIM trial used pharmaceutical GH, but the principles translate to the Natty Plus approach. MK-677 stimulates endogenous GH production, DHEA is available as an over-the-counter supplement, and berberine mimics many of metformin’s metabolic effects. A Natty Plus version of this protocol would look different in dosing and potency, but the mechanistic framework is the same. This is a direct application of the Tony Huge Laws of Biochemistry Physics—understanding the core biological levers (GH axis, hormonal precursors, insulin signaling) allows you to replicate a clinical outcome with different, more accessible tools.
This does not mean taking MK-677, DHEA, and berberine will definitely reverse your biological age. The TRIIM trial was small (9 participants) and used pharmaceutical-grade compounds at specific doses under medical supervision. But it provides a compelling proof-of-concept that targeting these three axes — growth hormone, hormonal support, and insulin sensitivity — can produce measurable anti-aging effects.
Other Supplements That Impact Hallmarks of Aging
Beyond the TRIIM protocol, several supplements have demonstrated effects on recognized hallmarks of aging. NMN and NR (nicotinamide riboside) boost NAD+ levels, which decline with age and are critical for cellular energy and DNA repair. Rapamycin (though pharmaceutical, not a supplement) is the most studied longevity compound in animal models, acting through mTOR inhibition. Resveratrol and pterostilbene activate sirtuins, another class of longevity-associated proteins.
The Natty Plus approach to longevity is the same as its approach to performance — evaluate each compound individually, track biomarkers, use conservative doses, and let the data guide your decisions. The goal is not to take everything on this list. The goal is to identify which interventions produce measurable improvements in your specific biology. For a broader look at the endgame of this research, explore the concept of Longevity Escape Velocity.
Interesting Perspectives
While the TRIIM trial is a landmark, the biohacking community is exploring adjacent and unconventional angles on age reversal. Some practitioners are layering the TRIIM-inspired protocol with senolytic compounds to clear aged “zombie” cells, theorizing a synergistic effect on epigenetic age. Others point to the potential of peptides like BPC-157 (despite regulatory challenges) for systemic repair and reducing inflammatory age, suggesting it could be a powerful adjunct to hormonal and metabolic interventions. There’s also a growing discussion around the role of advanced, non-supplement interventions. For instance, procedures like plasmapheresis (popularized by figures like Joe Rogan) aim to reduce circulating inflammatory and aging factors in the blood, representing a more aggressive, multi-modal approach to the same goal of reducing biological age. This aligns with a core Natty Plus principle: attack the problem from multiple validated pathways simultaneously.
Citations & References
- Fahy, G. M., et al. (2019). Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell. (The original TRIIM trial publication).
- Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology. (The epigenetic clock methodology).
- López-Otín, C., et al. (2013). The Hallmarks of Aging. Cell. (Foundational paper on aging theories).
- Bitto, A., et al. (2016). Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. (Key study on rapamycin and longevity).
- Yoshino, J., et al. (2018). NAD⁺ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metabolism. (Review on NAD+ boosters).