1. Scope

Scope — what is covered:

• Evidence-based prevention and reduction of frailty, sarcopenia and falls in adults seen in a private/independent UK longevity clinic, adjunctive to (not replacing) NHS primary and secondary care.
• Core guideline-based interventions (exercise, comprehensive geriatric assessment [CGA], medication optimisation, protein/nutrition, targeted vitamin D) and their evidence grade.
• Emerging and off-label “geroscience” interventions marketed within longevity practice (metformin, senolytics, NAD⁺ precursors, urolithin A, testosterone/SARMs, circadian/light strategies) with explicit evidence flags.
• Baseline work-up, ageing-biomarker use, monitoring, safety and practical clinic scenarios.

What is NOT covered:

• Acute management of an injurious fall, fracture fixation, or inpatient delirium pathways.
• Osteoporosis pharmacotherapy (bisphosphonates, denosumab, romosozumab) — cross-refer to bone-health guidance.
• Paediatric, pregnancy and end-of-life frailty care.
• Interventions with only animal/in-vitro data are confined to a clearly marked preclinical subsection and are not recommended for clinical use.

Key framing: In a longevity setting, most guideline-based frailty/falls interventions are legitimate preventive care; most “anti-ageing” pharmacological agents are off-label or research-only, and surrogate biomarker changes (e.g. epigenetic clocks) must not be presented to patients as proven reductions in falls, disability or mortality.

---

2. Background and pathophysiology

Frailty is a state of reduced physiological reserve and impaired resilience to stressors, operationalised either as the Fried phenotype (weight loss, weakness, slow gait, exhaustion, low activity) or the Rockwood deficit-accumulation index/Clinical Frailty Scale (Allison et al., AFP, 2021; Kim & Rockwood, NEJM, 2024). Falls are both a consequence and an accelerant of frailty; roughly one-third of people ≥65 and half of those ≥80 fall each year, and 1-year mortality after hip fracture approaches 31% (Nelson et al., AFP/NICE, 2026).

Biological rationale relevant to ageing (geroscience hypothesis): Age-related decline arises from interlinked “hallmarks of ageing” — chronic inflammation, cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, epigenetic change, stem-cell exhaustion and proteostasis loss (Tchkonia et al., JCEM, 2021; Partridge et al., Nat Rev Drug Discov, 2020). The hypothesis holds that targeting these shared mechanisms may compress morbidity, but this remains largely unproven for hard clinical endpoints in humans (Espinoza et al., J Gerontol A, 2023; Kritchevsky & Cummings, JAMA, 2025).

Mechanisms most relevant to frailty/falls with the strongest human signal:

• Sarcopenia / anabolic resistance: reduced muscle protein synthesis in response to protein and exercise underlies weakness and slow gait; addressed by resistance training + protein (Kim & Rockwood, NEJM, 2024).
• Circadian disruption: decreased rest–activity rhythm strength/stability prospectively predicts incident frailty (Cai et al., Nat Commun, 2023).
• Inflammation and nutrient sensing: IL-6, CRP, TNF-α, IGF-1, GDF-15 are the most reproducibly frailty-associated circulating markers in humans (Gonçalves et al., Ageing Res Rev, 2022).

Preclinical only (mechanistic plausibility, NOT clinical evidence): senolytic clearance of senescent cells, NAD⁺-precursor restoration of mitochondrial function, mitochondrial uncouplers and mitochondrial-derived peptides improve healthspan in rodents but lack confirmatory human functional-outcome trials (Tchkonia et al., 2021; Broome et al., Sports Med, 2024). Treat all of these as hypothesis-generating.

---

3. Evidence base and grading

Study types available range from Cochrane systematic reviews and large RCTs (exercise, falls, vitamin D, protein/resistance training, testosterone) to single RCTs and prospective cohorts for emerging agents, down to mechanistic/preclinical data for most geroscience drugs. Key clinical outcomes studied: rate of falls, risk of falling, fractures, mobility/gait speed, muscle strength, ADL, frailty phenotype status, hospitalisation and mortality. Biomarker/surrogate endpoints (epigenetic age acceleration, mitochondrial markers) are reported but not validated as causal intermediaries for falls or disability.

GRADE-style summary by outcome:

Intervention → Outcome	Certainty (GRADE)	Evidence statement	Strength of recommendation
Exercise (balance/strength/gait) → falls	Moderate–High	Cochrane and USPSTF: exercise reduces rate of falls (RaR ~0.68) and risk of falling; benefit lost if not sustained (high-certainty null on cessation)	Strong — offer
CGA / multidisciplinary intervention → frailty, hospital falls	Moderate–High	High-certainty reduction in Fried phenotype and hospital falls; reduces nursing-home admission	Strong — offer/refer
Protein + resistance training → lean mass, strength	Moderate	Network + pairwise meta-analyses: combination > either alone for lean mass/function; protein adds to RE especially in sarcopenic/frail	Strong — offer
Medication optimisation (deprescribing) → falls	Very low–High (setting-dependent)	High-certainty falls reduction in nursing homes; uncertain/low certainty community	Conditional — offer (esp. psychoactives)
Vitamin D → falls	Moderate (deficient only); D-recommendation (replete)	Reduces fall rate only where baseline levels low; USPSTF recommends against routine use in replete, non-osteoporotic	Conditional — only if deficient; recommend against routine
Testosterone (hypogonadal men) → lean mass/strength	Moderate	Consistent gains in lean mass and strength; inconsistent gait-speed/disability benefit; long-term CV/prostate safety not fully established	Conditional — only in biochemical hypogonadism
Metformin → physical performance/frailty (non-diabetic)	Moderate (for null/harm signal)	MET-PREVENT RCT: no gait-speed benefit, poorly tolerated, more hospital admissions; DPPOS: no frailty reduction vs placebo	Recommend against (outside trials)
Urolithin A → muscle endurance	Low–Moderate	Single 4-month RCT (n=66): improved muscle endurance and mitochondrial biomarkers; no 6-min walk benefit	Only in research / conditional adjunct
Light/circadian optimisation → sleep, frailty	Low	SR of light therapy improves sleep in LTC; frailty is a surrogate/prospective association only (Cai)	Only in research / low-risk adjunct
Senolytics, NAD⁺ precursors → frailty/falls	Very low	Human functional-outcome data absent or mixed; mechanistic/preclinical	Only in research

Common GRADE downgrades across emerging interventions: indirectness (surrogate endpoints, non-frail populations), imprecision (small single trials), inconsistency (high I² in exercise and protein pools), and risk of bias (unblinded/open-label longevity studies). Publication bias is a specific concern for supplement and geroscience literature.

---

4. Patient selection and indications

Who may benefit (inclusion):

• Adults ≥65, and 50–64 with a falls risk factor (diabetes, arthritis, dementia, Parkinson’s, learning disability, prior stroke) — the NICE 2026 falls-assessment population.
• Anyone with ≥2 falls in 12 months, a fall needing medical/surgical treatment, fall with loss of consciousness, inability to rise, or living with frailty → full comprehensive falls assessment.
• Prefrail/frail patients by CFS/Fried phenotype, low gait speed (<0.8 m/s), or probable sarcopenia (low grip: <27 kg men, <16 kg women; or 5× sit-to-stand >15 s).
• Middle-aged adults with high cardiometabolic risk seeking primary prevention: prioritise exercise, protein, weight/metabolic optimisation over unproven agents.

Exclusion / high-risk groups (avoid or specialist input):

• Unstable cardiac disease, recent MI/decompensated heart failure — before intensive exercise prescription.
• Symptomatic aortic stenosis, uncontrolled arrhythmia, acute illness.
• For testosterone: history of prostate/breast cancer, unevaluated PSA elevation, erythrocytosis, untreated severe OSA, active desire for fertility, thrombophilia.
• For metformin: eGFR <30, and generally not indicated for frailty per current RCT evidence.
• Cognitive impairment limiting consent — involve family/GP.

Regulatory and ethical status:

• On-label / guideline-based: exercise, CGA/multifactorial intervention, medication review, vitamin D (if deficient), protein/nutrition. These form the backbone of any longevity frailty programme.
• Off-label but rational in defined biochemical deficiency: testosterone in confirmed hypogonadism (Endocrine Society criteria).
• Off-label / research-only: metformin, senolytics (dasatinib+quercetin, fisetin), NAD⁺ precursors, urolithin A, SARMs, systematic epigenetic-clock–guided dosing. Offer only within trial frameworks/registries or as explicitly consented adjuncts, never as proven anti-frailty therapy.

---

5. Assessment and baseline work-up

History and examination:

• Falls history (number, mechanism, injury, loss of consciousness, ability to rise), fear of falling, footwear, home hazards, alcohol/substance use.
• Full medication review flagging psychoactives, sedatives, antihypertensives, anticholinergics, hypoglycaemics (STOPP/START, Beers).
• Orthostatic BP, vision, cognition, continence, mood, nutritional status/weight loss.

Validated tools:

• Frailty: Clinical Frailty Scale or Fried phenotype; PRISMA-7.
• Function: gait speed (4-m), Short Physical Performance Battery, Timed Up-and-Go (screen for gait/balance impairment — note NICE: does not reliably predict future falls, and NICE recommends against risk-prediction tools used in isolation).
• Sarcopenia: grip dynamometry, 5× sit-to-stand.

Baseline investigations (tailored):

• Bloods: FBC, U&E/eGFR, LFTs, HbA1c/fasting glucose, calcium/phosphate, 25-OH vitamin D, TFTs, B12/folate; testosterone (two morning samples with LH/SH BG, PSA, haematocrit) only if hypogonadism clinically suspected.
• Consider CRP/IL-6 as research-context inflammatory markers (not for routine decision-making).
• DXA for body composition/bone density where sarcopenia or osteoporosis suspected.

Ageing biomarkers (optional, research/monitoring context only): DNA-methylation clocks — GrimAge acceleration and DunedinPACE show the most consistent association with frailty and partially mediate the frailty–mortality link, but no clock is validated to guide therapy or predict falls, and DNAm age/age-deviation clocks show no frailty association (Tay et al., Lancet Healthy Longev, 2026; Beydoun et al., BMC Med, 2026; Kuiper et al., J Gerontol A, 2023). Document as exploratory; do not infer clinical benefit from clock changes.

Risk stratification:

• Low risk: no falls or single fall without gait/balance impairment → activity advice.
• Moderate: gait/balance impairment or single injurious fall → exercise programme + home-hazard assessment.
• High: ≥2 falls, injurious/syncopal fall, frailty → full CGA-style multifactorial assessment ± specialist referral.

Baseline documentation for follow-up: gait speed, grip, SPPB, CFS/Fried score, weight/BMI, protein intake (g/kg/day), vitamin D level, medication list, falls count, and (if used) baseline biomarker panel.

---

6. Dosing regimens and practical implementation

Robust human data — first-line:

• Exercise (strongest single intervention): structured programme combining balance, strength (resistance) and gait training, typically 1–4 sessions/week, 30–60 min, sustained indefinitely (benefit is lost on cessation — high-certainty). Tai chi and yoga improve balance/strength. Prescribe progressive resistance training targeting major muscle groups 2–3×/week.
• Protein: 1.0–1.2 g/kg/day for healthy older adults; 1.2–1.5 g/kg/day for those with acute/chronic illness or malnutrition risk (avoid in CKD without renal input). Distribute across meals; ingest protein in temporal proximity to resistance exercise. Protein adds to resistance training for lean mass/grip, especially in sarcopenic/frail patients; protein alone (without exercise) has minimal benefit.
• Vitamin D: replace only if deficient (e.g. <25–30 nmol/L); standard UK dosing (e.g. 800–2000 IU/day maintenance, or loading if profoundly deficient). Do not give routinely to prevent falls in replete, non-osteoporotic patients.
• CGA / multifactorial intervention: individualised, tailored to circumstances, with medication optimisation, home-hazard assessment, vision, footwear and postural-hypotension management — tailored delivery yields larger falls reductions.

Off-label / biochemical-deficiency use:

• Testosterone (hypogonadal men only): transdermal gel (~5–10 g/day) or IM (e.g. testosterone undecanoate/enantate per SmPC), titrated to mid-normal total testosterone. Gains in lean mass/strength are dose-dependent; gait-speed/disability benefit inconsistent. Not indicated to treat frailty per se in eugonadal men.

Regimens requiring caution (early-phase/single-trial data — adjunct or research only):

• Urolithin A: 1000 mg/day orally, 4 months improved muscle endurance and mitochondrial biomarkers in one RCT; no walk-distance benefit. Reasonable low-risk adjunct with informed consent, not a substitute for exercise.
• Creatine / omega-3 / GlyNAC / MitoQ: mechanistic and small-trial support only; may modestly support exercise adaptation — frame as adjunct with uncertain functional benefit.
• Light/circadian: morning bright light 2500–10 000 lux, 30–120 min improves sleep in long-term-care residents; daytime melanopic light targets are under active RCT investigation (LightSPAN). Reasonable, low-harm; frailty benefit unproven.

Recommend against outside trials:

• Metformin for frailty/performance in non-diabetics (MET-PREVENT: no benefit, poorly tolerated).
• Senolytics (dasatinib+quercetin, fisetin) and NAD⁺ precursors (NR, NMN): no validated dosing for frailty; research settings only.

---

7. Monitoring, safety and follow-up

Monitoring plan:

• Clinical/functional: repeat gait speed, grip, SPPB, CFS/Fried, weight, falls diary, fear-of-falling.
• Exercise programme: adherence, adverse musculoskeletal events, progression of load.
• Protein: renal function if higher intakes; dietary adherence (g/kg/day).
• Vitamin D: recheck 25-OH D and calcium after replacement.
• Testosterone: total testosterone, haematocrit (stop/reduce if >54%), PSA and DRE, lipids and symptoms at 3–6 and 12 months then annually.
• Metformin (if ever used): renal function, B12, GI tolerance.
• Ageing biomarkers: optional serial epigenetic clocks — interpret as exploratory only.

Timepoints: review at 3–4 months (functional response, tolerability), 6–12 months (sustained benefit, re-stratify), then annually with re-screening for falls and frailty.

Adverse effects:

• Exercise/multifactorial: harms are small (USPSTF); mainly minor musculoskeletal.
• Vitamin D: small-to-moderate net harm at population level when routine; hypercalcaemia at high doses.
• Testosterone: erythrocytosis, acne/fluid retention, potential OSA worsening; long-term CV and prostate safety not fully established.
• Metformin: GI intolerance common; in MET-PREVENT more hospital admissions in the metformin arm; B12 deficiency long-term.
• Urolithin A: well tolerated in trials; long-term safety data limited.

Actions for abnormal findings: rising falls/declining gait speed → escalate to full CGA / geriatrics referral; haematocrit >54% or PSA rise on testosterone → hold and refer; new syncope/postural drop → medication review and cardiovascular/autonomic assessment.

Interactions: additive fall risk from sedatives/antihypertensives/anticholinergics/hypoglycaemics — deprescribe where possible; testosterone may affect anticoagulant effect and glycaemic control; polypharmacy amplifies harm in frailty.

Special populations: avoid these agents in pregnancy/breastfeeding; dose-adjust or avoid metformin in renal impairment (eGFR <30) and testosterone with caution in hepatic disease; in advanced frailty and extreme old age prioritise low-harm interventions (exercise, deprescribing, nutrition) and shared goals of care.

---

8. Contraindications and cautions

Absolute contraindications:

• Testosterone: active prostate or breast cancer, untreated severe erythrocytosis, unevaluated prostate nodule/PSA.
• Any intensive exercise: unstable angina, decompensated heart failure, symptomatic severe aortic stenosis, uncontrolled arrhythmia, acute febrile illness.
• Vitamin D: hypercalcaemia.

Relative contraindications / specialist advice:

• Testosterone: severe untreated OSA, thrombophilia, desire for fertility, poorly controlled heart failure.
• Metformin: eGFR 30–45, conditions predisposing to lactic acidosis; overall not recommended for frailty.
• High-protein diets in chronic kidney disease.

Where harm likely outweighs benefit with current evidence:

• Routine vitamin D to prevent falls in replete, non-osteoporotic adults (USPSTF D-recommendation).
• Metformin, senolytics, NAD⁺ precursors and SARMs prescribed as proven anti-frailty therapy outside research — evidence does not support benefit and some show harm/intolerance.
• Presenting epigenetic-clock improvements to patients as proven reductions in falls, disability or death.

---

9. Practical management scenarios (CKS-style)

Scenario A — Middle-aged adult (55) with cardiometabolic risk seeking prevention

• Recommendation: Offer lifestyle-based prevention (Strong). Avoid metformin/senolytics for “anti-ageing” (Recommend against / research only).
• Assessment: baseline gait speed, grip, body composition, metabolic bloods, medication review.
• Shared decision-making: frame exercise + protein + metabolic optimisation as the evidence-based core; explicitly label geroscience drugs as unproven.
• Initiation: progressive resistance + aerobic + balance training ≥2–3×/week; protein 1.0–1.2 g/kg/day; treat vitamin D only if deficient; optimise BP/glucose/weight.
• Monitoring: 3–6 monthly function and metabolic review.
• Escalate/stop: refer if new falls, rapid functional decline, or cardiac symptoms with exercise.

Scenario B — Older frail patient (82) with multimorbidity and recurrent falls

• Recommendation: Offer comprehensive multifactorial (CGA-style) assessment and tailored exercise (Strong); restrict geroscience drugs to research only.
• Assessment: full falls assessment (history, orthostatic BP, vision, cognition, footwear, home hazards), CFS/Fried, medication review (STOPP/START).
• Shared decision-making: align with goals of care; involve family/GP.
• Initiation: tailored strength/balance/gait programme; deprescribe psychoactives/culprit drugs; home-hazard modification; ensure adequate protein; vitamin D if deficient; refer to geriatric/falls service.
• Monitoring: falls diary, gait speed, 3-monthly review.
• Escalate/stop: injurious/syncopal falls → cardiovascular/autonomic workup and geriatrics referral; stop any poorly tolerated agent.

Scenario C — Patient already under specialist care wanting a longevity adjunct

• Recommendation: Consider low-harm adjuncts (e.g. structured exercise coaching, protein optimisation, sleep/circadian and light strategies) alongside specialist care (Conditional); coordinate with the treating team; avoid duplicative or interacting off-label drugs.
• Assessment: reconcile full medication list; confirm no contraindications; document specialist plan.
• Shared decision-making: written informed consent for any off-label/research-only adjunct (e.g. urolithin A), with explicit statement that functional benefit is unproven.
• Initiation: add only interventions with a favourable harm profile and no interaction with specialist therapy.
• Monitoring: shared monitoring with specialist; track function and safety.
• Escalate/stop: any adverse interaction, biochemical abnormality, or patient preference change → stop and communicate with the specialist team.

---

10. Research gaps and future directions

• Hard-endpoint efficacy of geroscience drugs: whether metformin, senolytics, NAD⁺ precursors or rapamycin/rapalogs reduce falls, disability or mortality in humans is unresolved; MET-PREVENT was negative and DPPOS showed no frailty benefit for metformin.
• Optimal exercise/protein “dose”: the most effective exercise composition, intensity and protein timing/threshold for frail versus prefrail versus robust older adults remain undefined; heterogeneity is high.
• Biomarker validation: whether epigenetic clocks (GrimAge, DunedinPACE) or inflammatory/metabolomic markers can guide intervention selection or serve as trial surrogates for falls/disability needs prospective, harmonised, longitudinal validation; current linkage is associative.
• Circadian/light interventions: ongoing RCTs (e.g. LightSPAN) will clarify whether optimising light exposure translates from sleep/surrogate improvement into frailty/falls reduction.
• Emerging muscle-targeted agents: SARMs, urolithin A and other mitochondrial-targeted compounds require larger, longer trials with functional (not just biomarker) endpoints and long-term safety data.
• Recommended stance: outside guideline-based exercise, CGA, medication optimisation, protein and targeted vitamin D, off-label anti-ageing interventions for frailty/falls should be confined to well-designed clinical trials or prospective registries with informed consent.

Footnote: How the evidence supports this guideline

The backbone recommendations are anchored in the strongest available data: the 2025 Cochrane review and 2018 USPSTF review establish that exercise reduces falls (moderate–high certainty) while routine vitamin D does not benefit replete adults, and the Kim & Rockwood[1][2] NEJM review and NICE-derived falls guidance frame CGA, tailored multifactorial intervention and medication optimisation as the highest-yield strategies.[4][5][6] Muscle-focused nutrition recommendations (protein 1.0–1.5 g/kg/day plus resistance training) draw on four concordant meta-analyses.[7][8][9][18] The document deliberately flags the emerging agents conservatively: metformin is graded “recommend against” outside trials on the strength of the negative MET-PREVENT RCT and null DPPOS frailty data; testosterone is confined to biochemical hypogonadism per the Endocrine Society guideline and meta-analysis showing strength gains but inconsistent gait/disability benefit; urolithin A rests on a single RCT; and senolytics/NAD⁺ precursors remain research-only per geroscience reviews.[11][19][20][10][21][12][13][22][14][15] Ageing biomarkers (GrimAge, DunedinPACE) are presented as associative and non-actionable per the 2026 meta-analyses, honouring the instruction not to infer hard clinical benefit from surrogates.[16][17][23]

Two caveats for point-of-care use: several emerging-intervention grades are setting- and population-dependent (e.g. medication deprescribing shows high-certainty falls reduction in nursing homes but low certainty in the community), and the off-label agents lack long-term safety data — informed consent and coordination with the patient’s NHS team are essential.[1][4]

Figure 1 Rate Ratios (All Falls) for Selected Fall-Prevention Interventions vs Control in Community-Dwelling Older Peoplea Robertson MC, Gillespie LD. Fall Prevention in Community-Dwelling Older Adults. Jama. 2013;309(13):1406-7. doi:10.1001/jama.2013.3130.

 

Table 1 Evidence for Interventions to Prevent or Ameliorate Frailty and Associated Clinical Outcomes.* Kim DH, Rockwood K. Frailty in Older Adults. The New England Journal of Medicine. 2024;391(6):538-548. doi:10.1056/NEJMra2301292.

 

Figure 2 Outcomes on physical functioning and nutritional status. van den Helder J, Mehra S, van Dronkelaar C, et al. Blended Home-Based Exercise and Dietary Protein in Community-Dwelling Older Adults: A Cluster Randomized Controlled Trial. Journal of Cachexia, Sarcopenia and Muscle. 2020;11(6):1590-1602. doi:10.1002/jcsm.12634.

 

Figure 2 Box and Whisker Plots of the Effects of Testosterone Replacement Therapy and Placebo on Whole Body and Regional Lean Mass, Muscle Strength, Physical Function, and Aerobic Performance Bhasin S, Burnett AL, Gagliano-Jucá T, et al. Testosterone Treatment in Prostate Cancer Survivors With Hypogonadism: A Randomized Clinical Trial. JAMA Internal Medicine. 2026;:2848537. doi:10.1001/jamainternmed.2026.1343.

 

References

1. Interventions for Preventing Falls in Older People in Care Facilities. Dyer SM, Kwok WS, Suen J, et al. The Cochrane Database of Systematic Reviews. 2025;8:CD016064. doi:10.1002/14651858.CD016064.
2. Interventions to Prevent Falls in Community-Dwelling Older Adults. US Preventive Services Task Force, Grossman DC, Curry SJ, et al. JAMA. 2018;319(16):1696-1704. doi:10.1001/jama.2018.3097.
3. Fall Prevention in Community-Dwelling Older Adults. Robertson MC, Gillespie LD. JAMA. 2013;309(13):1406-7. doi:10.1001/jama.2013.3130.
4. Frailty in Older Adults. Kim DH, Rockwood K. The New England Journal of Medicine. 2024;391(6):538-548. doi:10.1056/NEJMra2301292.
5. Fall Prevention in Older Adults: Updated Guidelines From NICE. Nelson M, Lai A, Harding M. American Family Physician. 2026;113(6):608-610.
6. Clinical practice guidelines for the prevention and management of frailty: A systematic review. Zheng L, Li G, Qiu Y, et al. Journal of Advanced Nursing. 2022;78(3):709-721. doi:10.1111/jan.15067.
7. Comparison of the Effectiveness of Protein Supplementation Combined With Resistance Training on Body Composition and Physical Function in Healthy Elderly Adults. Tian H, Qiao W, Wen X. The Journal of Nutrition. 2025;155(3):764-774. doi:10.1016/j.tjnut.2025.01.017.
8. Protein Interventions Augment the Effect of Resistance Exercise on Appendicular Lean Mass and Handgrip Strength in Older Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Kirwan RP, Mazidi M, Rodríguez García C, et al. The American Journal of Clinical Nutrition. 2022;115(3):897-913. doi:10.1093/ajcn/nqab355.
9. Effects of Protein Supplementation Associated With Resistance Training on Body Composition and Muscle Strength in Older Adults: A Systematic Review of Systematic Reviews With Meta-Analyses. Vieira AF, Santos JS, Costa RR, Cadore EL, Macedo RCO. Sports Medicine (Auckland, N.Z.). 2022;52(10):2511-2522. doi:10.1007/s40279-022-01704-0.
10. Effects of Testosterone Replacement Therapy on Muscle Strength in Older Men With Low to Low-Normal Testosterone Levels: A Systematic Review and Meta-Analysis. Lee TW, Kao PY, Chen YC, Wang ST. Gerontology. 2023;69(10):1157-1166. doi:10.1159/000532062.
11. Metformin and Physical Performance in Older People With Probable Sarcopenia and Physical Prefrailty or Frailty in England (MET-Prevent): A Double-Blind, Randomised, Placebo-Controlled Trial. Witham MD, McDonald C, Wilson N, et al. The Lancet. Healthy Longevity. 2025;6(3):100695. doi:10.1016/j.lanhl.2025.100695.
12. Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial. Liu S, D’Amico D, Shankland E, et al. JAMA Network Open. 2022;5(1):e2144279. doi:10.1001/jamanetworkopen.2021.44279.
13. Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop. Espinoza SE, Khosla S, Baur JA, de Cabo R, Musi N. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2023;78(Suppl 1):53-60. doi:10.1093/gerona/glad034.
14. The Quest to Slow Ageing Through Drug Discovery. Partridge L, Fuentealba M, Kennedy BK. Nature Reviews. Drug Discovery. 2020;19(8):513-532. doi:10.1038/s41573-020-0067-7.
15. Geroscience. Kritchevsky SB, Cummings SR. JAMA. 2025;334(12):1094-1102. doi:10.1001/jama.2025.11289.
16. Biological Age Measured by DNA Methylation Clocks and Frailty: A Systematic Review and Meta-Analysis. Tay JH, Barros D, Wang W, Wazny VK, Maier AB. The Lancet. Healthy Longevity. 2026;:100773. doi:10.1016/j.lanhl.2025.100773.
17. Epigenetic Aging Markers in the Association Between Frailty and Mortality Among U.S. Adults. Beydoun MA, Noren Hooten N, Beydoun HA, et al. BMC Medicine. 2026;24(1):323. doi:10.1186/s12916-026-04866-0.
18. Effects of Protein Supplementation Combined With Resistance Exercise on Body Composition and Physical Function in Older Adults: A Systematic Review and Meta-Analysis. Liao CD, Tsauo JY, Wu YT, et al. The American Journal of Clinical Nutrition. 2017;106(4):1078-1091. doi:10.3945/ajcn.116.143594.
19. Association of Intensive Lifestyle and Metformin Interventions With Frailty in the Diabetes Prevention Program Outcomes Study. Hazuda HP, Pan Q, Florez H, et al. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2021;76(5):929-936. doi:10.1093/gerona/glaa295.
20. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. Bhasin S, Brito JP, Cunningham GR, et al. The Journal of Clinical Endocrinology and Metabolism. 2018;103(5):1715-1744. doi:10.1210/jc.2018-00229.
21. Testosterone Treatment in Middle-Aged and Older Men with Hypogonadism. Bhasin S, Snyder PJ. The New England Journal of Medicine. 2025;393(6):581-591. doi:10.1056/NEJMra2404637.
22. New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms. Tchkonia T, Palmer AK, Kirkland JL. The Journal of Clinical Endocrinology and Metabolism. 2021;106(3):e1481-e1487. doi:10.1210/clinem/dgaa728.
23. Epigenetic and Metabolomic Biomarkers for Biological Age: A Comparative Analysis of Mortality and Frailty Risk. Kuiper LM, Polinder-Bos HA, Bizzarri D, et al. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2023;78(10):1753-1762. doi:10.1093/gerona/glad137.
24. Blended home‐based exercise and dietary protein in community‐dwelling older adults: a cluster randomized controlled trial. van den Helder J, Mehra S, van Dronkelaar C, et al. Journal of Cachexia, Sarcopenia and Muscle. 2020;11(6):1590-1602. doi:10.1002/jcsm.12634.
25. Testosterone Treatment in Prostate Cancer Survivors With Hypogonadism. Bhasin S, Burnett AL, Gagliano-Jucá T, et al. JAMA Internal Medicine. 2026;:2848537. doi:10.1001/jamainternmed.2026.1343.