What trial designs and baseline assessments are needed to target supplements to older adults most likely to benefit?
Executive summary
Targeting supplements to older adults who will benefit most requires randomized, controlled trials that combine mechanistic biomarkers with geriatric functional phenotyping, stratify by frailty and baseline biology, and use adaptive, multi-stage designs to define dose, timing, and responder profiles; these elements are evident across recent Mitopure, NAD+ and GlyNAC trials and consensus guidance on older-adult research [1] [2] [3] [4].
1. What the trials should look like: randomized, blinded, placebo-controlled and adaptive
High-quality evidence in older adults comes from double-blind, placebo-controlled randomized trials that can detect both tolerability and mechanistic effects—examples include Mitopure’s double-blind placebo trials and NR studies that assessed NAD+ metabolism in middle-aged and older adults [1] [2]; pragmatic adaptations such as interim analyses and adaptive endpoints have precedent in nutritional trials where uncertain event rates required design changes and multiplicity adjustments [5], and exploratory pilot studies remain essential to map onset, peak effect, and durability before large-scale efficacy trials [6].
2. Who to enroll and how to stratify: frailty, baseline function, and real-world diversity
Meaningful targeting demands enrolling the heterogeneity of aging rather than a narrow “healthy older adult” cohort: frailty measures and baseline cognitive or functional status modify responses to interventions (for example, frail adults respond differently to blood-pressure targets) and should be prespecified stratifiers or effect modifiers in analysis plans [7]; inclusion strategies must also address recruitment, remote assessments, and special consent considerations unique to older populations, as outlined in guidance for trials in older adults [4] [7].
3. Baseline clinical and functional assessments to predict benefit
Trials should collect standardized geriatric measures—short physical performance battery, handgrip strength, gait speed, activities-of-daily-living and fatigue scales—at baseline because functional endpoints frequently capture clinically meaningful change and are already used as primary or secondary outcomes in older-adult nutrition trials [5] [4]; repeated performance measures across short-term and longer follow-ups (e.g., 30–180 days) provide trajectories that reveal responders versus nonresponders [4].
4. Biomarkers and mechanistic readouts to define biological responders
To target supplements by biology, baseline and on-treatment biomarkers must map the pathway the supplement targets: mitochondrial function and immune hallmarks were central to Mitopure studies (Urolithin A) [1], NAD+ metabolites and related markers were used in NR trials [2], and intracellular glutathione, oxidative stress and mitochondrial flux were measured in GlyNAC trials [3]; blood chemistry panels and safety labs (lipids, metabolic profile, HbA1c, uric acid, homocysteine) are routine baseline and monitoring tools in supplement protocols [8].
5. Trial timing, endpoints, and dose-finding: exploratory lead-ins matter
Pilot lead-ins and short-duration mechanistic endpoints help define how fast an intervention works and the appropriate visit schedule—industry and academic writers advise exploratory studies to map onset, peak, and durability before committing to large endpoints [6]; cognition, immune cell composition, cardiometabolic markers, and physical function have all served as primary or proximal endpoints in recent supplement and geroscience trials [1] [9] [10].
6. Analysis plan: pre-specified subgroup tests, intercurrent events and combination treatments
Analysis strategies should prespecify subgroup analyses by frailty and baseline biomarker status, plan for intercurrent events common in older adults, and consider factorial or add-on designs to test supplements in combination with lifestyle or repurposed drugs—this reflects the field’s shift toward multi-target strategies and combination approaches in longevity research [10] [4]; importantly, the lack of universally accepted aging biomarkers remains a constraint and must temper claims about “targeting” until validated predictors are replicated [11].
7. Limitations, trade-offs and alternative viewpoints
While mechanistic biomarkers and functional phenotyping improve targeting, critics note translational gaps from small, short-term trials to population-level outcomes and emphasize that one trial is not enough—replication, larger diverse cohorts, and validation of predictive biomarkers are essential before clinical recommendations can be made [6] [11].