For years, collagen supplements have filled shelves and social media feeds, promising smoother skin, stronger joints, and a more youthful appearance. Yet despite the enthusiasm, one question has lingered: what exactly within collagen delivers those benefits?
A recent study published in npj Aging offers one of the most compelling answers to date. Researchers from ETH Zürich and collaborators across Europe and the US have identified a minimal, highly specific combination of amino acids—three glycine, one proline, and one hydroxyproline—that appears to reproduce and even enhance many of the health effects typically attributed to collagen supplementation.
Their findings span C. elegans, mice, human fibroblasts, and a 6-month observational human trial, making this one of the most comprehensive evaluations of collagen-related biology to date.
Why Collagen Matters for Ageing
Collagen is the scaffolding of our bodies, making up around 12–17% of total protein. As we age, the ability to produce and maintain collagen declines steadily, contributing to wrinkles, reduced elasticity, joint discomfort, and diminishing muscle resilience. The cosmetic and wellness industries have seized on this, propelling the global collagen market into the billions.
Still, a major blind spot has remained: once ingested, collagen is broken down into peptides and amino acids. So do whole collagen peptides matter—or is it the component amino acids that make the difference?
The study addresses this question head-on.
The Surprising Power of a 3:1:1 Amino Acid Ratio
Findings from C. elegans (roundworm) experiments
The researchers began by testing how collagen supplementation affects collagen gene activity during ageing in C. elegans. On its own, collagen produced only mild benefits. But when the worms were fed a precise mixture of 3 glycine : 1 proline : 1 hydroxyproline, their collagen expression remained higher for longer, and lifespan extended significantly—by 6–27% in independent trials.
Interestingly, feeding any single amino acid alone produced no meaningful benefit. It was the combination—and crucially, the ratio—that created a synergistic effect.
The team then tested a range of alternative ratios and confirmed that while several combinations could prolong lifespan, the 3:1:1 blend consistently delivered the greatest improvements in both survival and late-life mobility.
This suggests the body recognises this ratio as a biological signal linked to collagen homeostasis.
Synergy with Cellular Metabolism
Hydroxyproline formation in collagen requires the metabolic cofactor alpha-ketoglutarate (AKG), a well-known longevity-associated molecule. The researchers demonstrated that combining AKG with the 3:1:1 amino acid blend produces additive improvements in longevity in C. elegans.
This metabolic link may help explain why collagen-rich diets or collagen peptides often correlate with improved tissue repair and resilience in mammals.
Human Skin Cells Respond Rapidly
To understand how human cells react to the 3:1:1 mixture, the team exposed dermal fibroblasts to the blend for 2, 8, and 24 hours and analysed gene expression.
The results were striking:
Genes related to collagen synthesis and extracellular matrix (ECM) structure were strongly upregulated.
Genes associated with ribosomal and mitochondrial processes were downregulated—suggesting a shift in energy priorities towards tissue maintenance and repair.
The “matrisome” (the complete ECM gene network) showed broad activation, especially collagen-related domains.
In other words, human cells responded as though they were receiving a direct prompt to reinforce tissue integrity.
Testing in Aged Mice: Strength and Fat Levels Improve
Next, the researchers evaluated safety and physical effects in 20-month-old male mice (roughly equivalent to a 60–70-year-old human).
Over six months:
Mice receiving the 3:1:1 mixture did not show adverse effects.
They exhibited reduced visceral fat accumulation.
Their grip strength improved, counteracting typical age-related decline.
These findings mirror earlier work showing that collagen peptides can support muscle maintenance and body composition in older adults.
A Human Trial: Better Skin and a Drop in Biological Age
Building on the mechanistic and preclinical evidence, the team developed a more complete formulation—referred to as a “Collagen Activator”—combining:
- the 3:1:1 amino acid ratio,
- vitamin C (essential for collagen synthesis),
- astaxanthin (an antioxidant linked to collagen support), and
- alpha-ketoglutarate.
A total of 66 healthy adults aged 35–68 took the formulation for six months.
Skin outcomes (first 3 months)
Measured using clinical imaging and biophysical tools (Visia scans, Cutometer, Corneometer), the participants showed:
- Significantly improved skin texture
- 35% increase in cheek hydration on average
- Noticeable improvements in elasticity (R2 index)
- Progress in dryness, fine texture and overall skin quality
These changes were consistent across most participants and were generally evident after the first month.
Reduction in biological age (after 6 months)
Using the TruMe epigenetic clock:
- Biological age decreased by an average of 1.4 years.
- Men and women showed similar benefits.
- Some participants experienced reductions of 8–12 years.
Interestingly, those with a “biologically older” baseline tended to show the largest improvements—a trend observed in other epigenetic-age interventions.
How Might These Three Amino Acids Work?
Each amino acid has a distinct role:
Glycine
Abundant in collagen
Linked to improved metabolic health, reduced inflammation, and extended lifespan in models
Supports muscle progenitor cell function and fat metabolism
Proline
Essential for collagen structure
Functions in cellular stress response and mitochondrial repair pathways
Supports longevity pathways involving AMPK and FOXO transcription factors
Hydroxyproline
Stabilises collagen helices
Can convert into glycine in humans
Exhibits anti-inflammatory effects in animal models
Together, they form the fundamental repeating motif of collagen molecules. The study suggests that when provided in the correct proportions, they act as a molecular signal encouraging the body to maintain collagen integrity and broader ECM health.
Strengths, Caveats, and What Comes Next
Strengths
Multi-species validation: worms, mice, human cells, and human participants
Mechanistic investigations via gene expression
Clear dose–response relationships
Inclusion of functional measures (mobility, grip strength, hydration, elasticity, biological age)
Limitations
The human trial was observational, not placebo-controlled.
The cohort was unusually healthy and highly educated, which may limit generalisability.
More research is needed to determine whether the amino acid ratio alone—or the full Collagen Activator formulation—drives most of the biological age effect.
The authors emphasise the need for randomised controlled trials and deeper exploration of how cells detect and respond to the 3:1:1 ratio.
The Bigger Picture
This study provides one of the clearest mechanistic bridges yet between collagen supplementation and measurable improvements in biological ageing. The notion that the body may be tuned to detect a specific amino acid ratio—one that mirrors collagen’s structure—opens new avenues for nutritional strategies targeting skin health, metabolic wellbeing, and tissue maintenance.
While more rigorous clinical trials are needed, the results offer an exciting glimpse into a future where precise amino acid formulations could help support healthier ageing from the inside out.
The study is published in the journal npj Aging. It was led by Alexander Dakhovnik from ETH Zürich.
