Rethinking insulin resistance in aging: A reserve-oriented clinical framework (paper July 2026)

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https://www.sciencedirect.com/science/article/pii/S1568163726001728

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Summary

This is a narrative review arguing that insulin resistance in ageing should not be treated simply as defective glucose handling or a precursor to type 2 diabetes, but as a marker of declining metabolic resilience across muscle, adipose tissue, mitochondria, inflammatory systems, hormones, and the brain. The authors explicitly frame ageing-related insulin resistance as a multisystem loss of physiological reserve rather than an isolated insulin-signalling defect.

The paper’s core argument is built around three main tissue systems:

1. Skeletal muscle as the central vulnerability

The authors argue that ageing muscle is the dominant driver of late-life insulin resistance because skeletal muscle is the main site of postprandial glucose disposal. The key problem is not only sarcopenia, but loss of muscle quality: myosteatosis, mitochondrial dysfunction, reduced oxidative capacity, anabolic resistance, and impaired insulin-stimulated glucose uptake. This means an older person can have insulin resistance even without obesity if muscle metabolic reserve has declined.

2. Adipose tissue as an inflammatory amplifier

The review describes ageing adipose tissue as changing from a passive energy store into an endocrine and inflammatory organ. Visceral fat accumulation, adipose immune infiltration, adipocyte senescence, SASP signalling, reduced adipose expandability, and altered adipokines all amplify systemic insulin resistance. The paper stresses that this can occur even when BMI is not markedly elevated.

3. Brain insulin resistance as part of metabolic ageing

A major theme is that insulin resistance extends into the CNS. The authors link impaired brain insulin signalling to reduced cerebral glucose metabolism, neuroinflammation, synaptic dysfunction, cognitive decline, depression, and frailty. They argue that brain insulin resistance should be seen as downstream of systemic metabolic-resilience failure, not as a separate neurological phenomenon.

Mechanistically, the paper ties these tissue-level changes together through inflammageing, cellular senescence, mitochondrial dysfunction, impaired mitophagy, disrupted mitochondria–ER crosstalk, and hormonal dysregulation. The figures summarise this as a shift from a glucose/BMI-focused model to a reserve-oriented model that prioritises muscle function, inflammatory burden, brain health, body composition, and functional capacity.

Therapeutically, the authors argue for intervention aimed at preserving reserve rather than only lowering glucose. They emphasise resistance training, aerobic exercise, adequate protein, dietary quality, GLP-1 receptor agonists, SGLT2 inhibitors, bariatric surgery in selected cases, senotherapeutics, mitochondrial interventions, and intranasal insulin as possible components of a broader strategy. They also warn that in older adults, weight-loss drugs may worsen lean-mass loss unless paired with resistance training and protein support.

Novelty

The novelty is mainly conceptual rather than experimental. This is not a new dataset or systematic meta-analysis; it is a framework paper.

The most novel contribution is the “reserve-oriented” framing: insulin resistance is presented as a biomarker of declining physiological resilience across metabolic, musculoskeletal, inflammatory, and neurocognitive systems, rather than as a discrete glucose-regulatory defect.

A second useful novelty is the integration of frailty, sarcopenia, brain ageing, depression, and multimorbidity into the insulin-resistance framework. Many reviews focus on diabetes, obesity, or peripheral insulin signalling; this paper explicitly argues that late-life insulin resistance belongs in geroscience and geriatric medicine as much as in diabetology.

A third novel aspect is the therapeutic reframing: the clinical goal should not simply be lower glucose or lower body weight, but preservation of muscle function, metabolic flexibility, inflammatory control, and cognitive reserve. That is a useful corrective to glucose-centric and BMI-centric models, especially for older adults.

Critique

The main weakness is that the paper is a narrative review, so the strength of evidence varies substantially across its claims. The broad framework is plausible, but the review does not provide a formal search strategy, inclusion criteria, evidence grading, or quantitative weighting. As a result, it sometimes reads as a persuasive synthesis rather than a rigorous adjudication of competing evidence.

A second issue is that the paper may over-unify heterogeneous phenomena. “Insulin resistance” in muscle, liver, adipose tissue, brain, endothelium, and immune cells may not be the same biological process. Peripheral insulin resistance measured by HOMA-IR or clamp studies is not interchangeable with brain insulin resistance, frailty, or depression. The framework is attractive, but it risks treating insulin resistance as a general ageing signal rather than a precisely measurable mechanism.

Third, the causal direction remains incompletely resolved. The paper often implies that insulin resistance is a marker or driver of declining reserve, but in many cases it could also be a consequence of reduced activity, inflammation, adipose dysfunction, mitochondrial decline, disease burden, medication exposure, or acute illness. The authors do acknowledge context dependence, including the possibility that moderate insulin resistance in some older adults may not be uniformly harmful, but this point could have been developed more deeply.

Fourth, the therapeutic section is somewhat uneven. Resistance training and protein support have strong translational plausibility; senolytics, NAD⁺ precursors, exercise mimetics, mitochondrial interventions, and intranasal insulin are much more preliminary. The authors do note that senotherapeutics and mitochondrial-targeted approaches remain early-stage, with limited long-term evidence in older or frail populations, but the paper still groups mature and speculative interventions within the same broad model.

Finally, the paper could have been more precise about clinical implementation. A reserve-oriented model is useful, but clinicians would need operational thresholds: grip strength, gait speed, DXA or MRI body composition, inflammatory markers, CGM patterns, HOMA-IR, clamp-derived insulin sensitivity, cognitive tests, mitochondrial markers, or frailty indices. The paper gestures toward such integrated assessment, but does not provide a practical scoring system or decision algorithm.

Overall assessment

This is a strong conceptual geroscience review. Its value lies in reframing insulin resistance in older adults as part of a broader failure of muscle–adipose–brain metabolic resilience. The framework is clinically sensible and aligns well with the idea that ageing interventions should preserve function rather than merely normalise biomarkers.

The weakness is that the model is broader than the evidence base. It is best read as a hypothesis-generating clinical framework, not as proof that insulin resistance is the central causal mechanism of frailty, cognitive decline, or ageing-related multimorbidity.

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Digging into the potential actions suggested by this paper:

Actionable Insights

  • Prioritize Muscle Quality Over Weight Loss: Improvements in insulin sensitivity in older adults correlate far more robustly with gains in muscle quality and mitochondrial capacity than with simple body weight reduction. Lean, physically active older individuals can still exhibit profound insulin resistance if myosteatosis and mitochondrial decay are left unchecked.

  • Bypass Anabolic Resistance with Targeted Nutrition: Older adults exhibit severe anabolic resistance, requiring substantially higher per-meal protein doses to stimulate muscle protein synthesis. Diets must optimize the timing, distribution, and quality of protein alongside anti-inflammatory components and low glycemic loads to preserve the muscle metabolic buffer.

  • Deploy Progressive Resistance Training: Structured resistance training acts as a foundational tool to directly counteract sarcopenia, enhance mitochondrial oxidative capacity, and increase insulin-stimulated glucose uptake independently of total fat mass changes.

  • Exercise Extreme Caution with Longevity/Weight-Loss Therapeutics: While GLP-1 receptor agonists and SGLT2 inhibitors offer systemic metabolic benefits, they present severe risks for older or frail populations, including accelerated lean mass wasting and dehydration if used without concurrent resistance exercise and aggressive protein support.

  • Monitor Functional Biomarkers: Clinical screening must expand beyond standard fasting glucose and HbA1c to include functional measures of physiological reserve, such as muscle strength, body composition analysis, and physical/cognitive performance.

Actionable Interventions & Evidence Validation

1. SGLT2 Inhibition (Canagliflozin / Empagliflozin)

The Core Strategy

Sodium-glucose cotransporter-2 (SGLT2) inhibitors act as caloric restriction (CR) mimetics by blocking renal glucose reabsorption, inducing continuous glycosuria and subsequent nutrient-deprivation signaling. This downregulates the nutrient-sensing mechanistic target of rapamycin (mTOR) pathway via the activation of adenosine monophosphate-activated protein kinase (AMPK). The strategy shifts systemic metabolism away from carbohydrate dependency toward fatty acid oxidation and ketogenesis, reducing the advanced tissue lesions, chronic inflammaging, and macromolecular damage that compromise physiological reserve across the liver, kidneys, and heart.

Translational Dosing Protocol

  • Dosing Logic: Extrapolated from the National Institute on Aging (NIA) Interventions Testing Program (ITP) mouse protocol using 180 parts per million (ppm) of canagliflozin in chow, which yields an approximate daily consumption of 30 mg/kg/day.
  • Raw Math (BSA Normalization): HED = Animal Dose * (Animal Km / Human Km) HED = 30 mg/kg/day * (3 / 37) = 2.43 mg/kg/day For a 70 kg adult: 2.43 mg/kg/day * 70 kg = 170.1 mg/day
  • Clinical Protocol: Translated to a standard human maintenance dose of 100 mg to 300 mg orally once daily.
  • Pharmacokinetics: Oral bioavailability is approximately 65%; it exhibits a terminal elimination half-life of 10 to 13 hours, reaching steady-state plasma concentrations within 4 to 5 days of daily administration.

Literature Validation & Source Verification

The NIA ITP rigorously demonstrated that canagliflozin extended median lifespan by 14% and maximum lifespan by 9% in genetically heterogeneous male mice. Histopathological follow-ups confirmed that this lifespan extension was accompanied by a significant reduction in cardiomyopathy, glomerulonephropathy, and hepatic lipidosis. Central nervous system evaluations further established that canagliflozin treatment preserves hypothalamic and hippocampal insulin signaling while suppressing microgliosis and age-associated neuroinflammation.

Safety, Toxicity, & Interaction Profile

  • Safety Metrics: The No Observed Adverse Effect Level (NOAEL) in long-term rodent models is established at exposures exceeding 10 times the maximum recommended human dose (MRHD).
  • Toxicity Signals: Low risk of hepatotoxicity; however, renal monitoring is required due to transient reductions in estimated glomerular filtration rate (eGFR) upon initiation. Main safety signals include increased risk of genitourinary tract infections, volume depletion, hypotension, and euglycemic diabetic ketoacidosis (DKA).
  • CYP450 Interactions: Primarily metabolized via UGT1A9 and UGT2B4 glucuronidation; minimal interactions with cytochrome P450 pathways, though it may mildly increase plasma levels of co-administered digoxin.

Longevity Stack Compatibility

  • Rapamycin: Highly synergistic; combines dual-node mTOR inhibition via different upstream targets without compounding immunosuppression.
  • Metformin: Competes partly for AMPK activation pathways; combines well but increases risks of gastrointestinal distress and subclinical lactic acidosis.
  • Acarbose: Strong synergistic glucose-flattening effects; requires careful tracking to avoid severe hypoglycemia.
  • 17-Alpha Estradiol: Compatible; mimics the male-specific survival advantages seen in ITP evaluations.
  • PDE5 Inhibitors: Potentiates volume depletion; concurrent use requires strict blood pressure monitoring due to orthostatic hypotension risks.

2. Senolytic Therapy (Fisetin)

The Core Strategy

Fisetin is a naturally occurring flavonoid that acts as a potent, cell-type-specific senotherapeutic agent. It selectively induces apoptosis in senescent adipocytes and stromal vascular cells by inhibiting the Akt/mTOR cell-survival pathway and suppressing the expression of anti-apoptotic proteins. Clearing senescent cells breaks the destructive autocrine and paracrine feed-forward loops of the Senescence-Associated Secretory Phenotype (SASP), reducing local tissue fibrosis, preserving subcutaneous adipose tissue storage capacity, preventing lipotoxic lipid spillover into skeletal muscle, and lowering systemic low-grade inflammaging.

Translational Dosing Protocol

  • Dosing Logic: Based on the intermittent “hit-and-run” human clinical trial design pioneered by the Mayo Clinic to eliminate senescent cell accumulation without disrupting basal physiological tissue remodeling.
  • Clinical Protocol: 20 mg/kg/day taken orally for 2 consecutive days, repeated once per month or every 3 months. For a 70 kg human, this translates to a high dose of 1,400 mg daily for a 48-hour window.
  • Pharmacokinetics: Extremely low oral bioavailability (under 5%) due to rapid first-pass phase II glucuronidation in the intestine and liver. Terminal elimination half-life is short, ranging between 1.5 and 3 hours, which satisfies the hit-and-run pharmacological requirement.

Literature Validation & Source Verification

Translational studies confirmed that late-life administration of fisetin to wild-type mice significantly reduced senescence markers in multiple tissue types, restored organ homeostasis, decreased age-related histopathology, and extended both median and maximum lifespan. Intermittent fisetin treatment in aged human adipose tissue explants effectively cleared senescent adipocytes and suppressed the secretion of key SASP interleukins and matrix-remodeling enzymes. Long-term animal protocols also verified that intermittent fisetin halts age-related declines in grip strength and overall physical function.

Safety, Toxicity, & Interaction Profile

  • Safety Metrics: Human clinical trials utilizing high-dose intermittent regimens up to 20 mg/kg/day have reported no severe adverse events or toxicities.
  • Toxicity Signals: Animal safety models show a high margin of safety with no significant liver or kidney toxicities noted during intermittent use.
  • CYP450 Interactions: Fisetin acts as an inhibitor of CYP2C9 and CYP3A4 enzymes in vitro; caution must be exercised when taking medications with narrow therapeutic windows that rely on these clearance pathways during the active 2-day dosing window.

Longevity Stack Compatibility

  • Rapamycin: Use caution; both compound classes suppress the Akt/mTOR node. They should not be co-administered on the same days to prevent severe, prolonged immune or wound-healing impairment.
  • SGLT2 Inhibitors: Fully compatible; no known overlapping clearance or toxic mechanisms.
  • Metformin / Acarbose: Compatible; may enhance systemic anti-inflammatory actions.
  • 17-Alpha Estradiol / PDE5 Inhibitors: No documented negative interactions or contraindications.

3. Intranasal Insulin Delivery

The Core Strategy

Intranasal administration delivers insulin directly to the central nervous system (CNS) along extra-neuronal routes through the intercellular clefts of the olfactory and trigeminal nerve pathways. This targeted strategy completely bypasses the blood-brain barrier and avoids systemic circulation, preventing peripheral hypoglycemia. By directly binding to abundant insulin receptors within the hippocampus, prefrontal cortex, and hypothalamus, it reverses age-related brain insulin resistance. This enhances neuronal glucose hypometabolism, preserves local synaptic plasticity, reduces microglial priming and neuroinflammation, and prevents white matter hyperintensity progression.

Translational Dosing Protocol

  • Dosing Logic: Derived directly from successful Phase II human clinical trial protocols designed to rescue cognitive decline and brain hypometabolism.
  • Clinical Protocol: 20 IU (International Units) of regular human insulin (e.g., Humulin R) administered intranasally twice daily, for a total daily intake of 40 IU. This must be delivered via a specialized intranasal atomization device designed to target the olfactory epithelium.
  • Pharmacokinetics: Rapidly enters the cerebrospinal fluid (CSF) within 15 to 30 minutes. It does not alter peripheral blood glucose or systemic insulin concentrations at clinical doses, minimizing systemic side effects. Central receptor engagement half-life remains partially unmapped but dictates twice-daily administration.

Literature Validation & Source Verification

Multicenter, randomized, double-blind clinical trials using 40 IU daily of intranasal insulin for 12 months demonstrated a significant reduction in global and regional white matter hyperintensity progression in deep and frontal brain regions. This preservation of white matter architecture was strongly correlated with stabilized cognitive performance on the Alzheimer’s Disease Assessment Scale-Cognition and favorable modulations of CSF biomarker profiles in adults with amnestic mild cognitive impairment.

Safety, Toxicity, & Interaction Profile

  • Safety Metrics: Clinical trials have confirmed that long-term intranasal delivery at 40 IU/day does not cause systemic hypoglycemia or alter fasting peripheral HbA1c profiles.
  • Toxicity Signals: Localized adverse events are mild and restricted to nasal irritation, transient rhinitis, and minor epistaxis. There are no known hepatic, renal, or systemic toxicity signals.
  • CYP450 Interactions: Entirely independent of the cytochrome P450 enzyme matrix; degraded centrally via insulin-degrading enzyme (IDE).

Longevity Stack Compatibility

  • Rapamycin: Fully compatible; rapamycin’s peripheral metabolic side effects (transient insulin resistance) are bypassed, and its central neuroprotective attributes are complemented.
  • SGLT2 Inhibitors / Metformin / Acarbose: Highly compatible; central insulin sensitization operates via independent networks that complement peripheral glucose-lowering mechanisms without increasing the risk of systemic hypoglycemia.
  • 17-Alpha Estradiol / PDE5 Inhibitors: No known therapeutic conflicts.

4. NAD+ Precursor Optimization (Nicotinamide Riboside)

The Core Strategy

Oral nicotinamide riboside (NR) supplementation operates as an upstream metabolic intervention designed to rescue the age-associated decline of the nicotinamide adenine dinucleotide (NAD+) metabolome. NAD+ is an obligatory coenzyme required for mitochondrial oxidative phosphorylation, ATP generation, and organelle-level communication via Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs). Augmenting the intracellular NAD+ pool drives the catalytic activity of sirtuins (SIRT1/SIRT3) and poly(ADP-ribose) polymerases (PARPs), repairing genomic instability, enhancing mitochondrial biogenesis, and reducing the skeletal muscle transcriptomic and systemic inflammatory signatures that generate functional metabolic decline.

Translational Dosing Protocol

  • Dosing Logic: Derived directly from randomized, double-blind, crossover clinical trials validating bio-availability and metabolomic alterations in aged human tissue.
  • Clinical Protocol: 1,000 mg total daily dose taken orally, either as a single morning dose or divided into 500 mg twice daily.
  • Pharmacokinetics: Following ingestion, NR is rapidly converted into nicotinamide and other metabolites within the gastrointestinal tract and liver before being transformed into intracellular NAD+. Peak plasma and tissue metabolite concentrations occur 1 to 3 hours post-ingestion; terminal excretion products are cleared via renal methylation path networks.

Literature Validation & Source Verification

A randomized, double-blind, placebo-controlled crossover clinical trial in healthy aged men established that 1,000 mg/day of oral NR for 21 days effectively penetrated aged human skeletal muscle tissue. This intervention significantly elevated the muscle NAD+ metabolome and induced a distinct downregulation of pro-inflammatory transcriptomic signatures, resulting in a meaningful reduction of circulating systemic inflammatory cytokines.

Safety, Toxicity, & Interaction Profile

  • Safety Metrics: Human clinical trials demonstrate excellent tolerability up to 1,000–2,000 mg daily for extended durations.
  • Toxicity Signals: No liver transaminase elevations or renal filtration anomalies have been recorded at established human doses.
  • CYP450 Interactions: Does not inhibit or induce major CYP450 pathways. It is metabolized entirely via parallel salvage pathways and excreted via renal pathways as N-methylnicotinamide.

Longevity Stack Compatibility

  • Rapamycin: Highly compatible; counteracts the mitochondrial and lipid processing irregularities that can emerge during long-term rapamycin administration.
  • SGLT2 Inhibitors: Highly synergistic; combines SGLT2i-mediated nutrient deprivation signaling with direct mitochondrial coenzyme resuscitation.
  • Metformin: Synergistic; metformins AMPK-driven improvements in insulin sensitivity pair effectively with NR-mediated sirtuin activation.
  • Acarbose / 17-Alpha Estradiol / PDE5 Inhibitors: Fully compatible; no known overlapping toxicities or receptor competitions.

5. GLP-1 Receptor Agonism (Semaglutide)

The Core Strategy

Glucagon-like peptide-1 (GLP-1) receptor agonists act as long-acting incretin mimetics resistant to dipeptidyl peptidase-4 (DPP-4) degradation. Beyond slowing gastric emptying and driving central satiety via hypothalamic networks, GLP-1 receptor agonism suppresses systemic inflammaging by downregulating the chronic activation of the intracellular cGAS-STING innate immune signaling pathway. This prevents mitochondrial double-stranded DNA leakage into the cytosol, downregulates downstream NF-kappaB and NLRP3 inflammasome assembly, restores skeletal muscle mitochondrial oxidative phosphorylation capacity, and improves peripheral and central insulin sensitivity.

Translational Dosing Protocol

  • Dosing Logic: Derived from standardized, once-weekly clinical subcutaneous escalation and maintenance protocols designed to balance metabolic remodeling against gastrointestinal side effects.
  • Clinical Protocol: Initiated at 0.25 mg subcutaneously once weekly for 4 weeks; escalated to 0.5 mg weekly for 4 weeks; then titrated up to a maintenance longevity dose of 1.0 mg to 2.4 mg subcutaneously once weekly.
  • Pharmacokinetics: Subcutaneous bioavailability is high (~89%). It reaches maximum plasma concentrations 1 to 3 days post-injection and features a prolonged terminal elimination half-life of approximately 168 hours (7 days), enabling steady-state maintenance with once-weekly administration.

Literature Validation & Source Verification

Clinical and mechanistical evaluations have verified that semaglutide reduces chronic tissue inflammation through the activation of upstream AMPK/SIRT1 pathways and the simultaneous repression of downstream NF-kappaB cascades. Large-scale cardiovascular outcomes trials have documented significant, sustained relative risk reductions in major adverse cardiovascular events (MACE) and a powerful mitigation of chronic inflammatory trajectories independently of the degree of glycemic lowering.

Safety, Toxicity, & Interaction Profile

  • Safety Metrics: Features a well-established, large-scale safety profile, though it is strictly contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
  • Toxicity Signals: Black box warning for thyroid C-cell tumors based on rodent data. Notable risks include acute pancreatitis, acute kidney injury secondary to dehydration, cholelithiasis, and severe delayed gastric emptying (gastroparesis).
  • CYP450 Interactions: Does not induce or inhibit cytochrome P450 pathways. However, delayed gastric emptying can alter the rate of absorption of concurrently administered oral medications.

Longevity Stack Compatibility

  • Rapamycin: Potential risk; both compounds can alter gastrointestinal motility and suppress appetite. Co-administration requires meticulous monitoring to avoid severe muscle mass wasting (sarcopenia) and nutritional deficits.
  • SGLT2 Inhibitors: Synergistic; highly effective dual-mechanism cardiorenal and metabolic preservation, but significantly increases the risk of dehydration and hypotension.
  • Metformin / Acarbose: Compatible; however, it multiplies the cumulative risk of severe gastrointestinal side effects (nausea, diarrhea, cramping).
  • 17-Alpha Estradiol / PDE5 Inhibitors: Fully compatible; no competitive clearance or compounding adverse mechanisms identified.

Strategic Feasibility & Target Engagement

Biomarker Verification

To precisely verify that these interventions are engaging their intended biological targets and improving metabolic resilience, a targeted panel of downstream blood, tissue, and functional biomarkers must be measured before and during therapy:

Intervention Primary Mechanism Human Target Engagement Biomarkers
SGLT2 Inhibition Renal glucose clearance, AMPK activation, mTOR inhibition * Blood: β-hydroxybutyrate (Ketone body elevation), Fasting Insulin, and eGFR. * Urine: Quantitative 24-hour glucose excretion. * Intracellular: Phosphorylation status of AMPK and p70S6K in peripheral blood mononuclear cells (PBMCs).
Senolytic Therapy Apoptosis of senescent cells, SASP suppression * Blood: High-sensitivity IL-6, TNF-α, and circulating Matrix Metalloproteinases (MMP-3/MMP-9). * Cellular: Intracellular p16INK4a and p21CIP1 expression within biopsied adipose tissue or circulating T-lymphocytes.
Intranasal Insulin Cortical insulin signaling resensitization * Neuroimaging: 18F-FDG PET imaging showing a reversal of regional hippocampal and prefrontal cortex hypometabolism. * Fluid: Reduction of phosphorylated tau (p-tau181​/p-tau217​) and neurofilament light chain (NfL) in CSF or plasma.
NAD+ Precursors Mitochondrial coenzyme restoration * Blood/Tissue: Absolute quantitative liquid chromatography-mass spectrometry (LC-MS) assays measuring total intracellular NAD+, NADH, and nicotinic acid adenine dinucleotide (NAAD) pools in whole blood or muscle biopsies.
GLP-1 Receptor Agonism Incretin signaling, cGAS-STING down-regulation * Blood: High-sensitivity C-reactive protein (hs-CRP), fasting plasma glucagon, and postprandial insulin. * Body Composition: Dual-energy X-ray absorptiometry (DEXA) verifying fat-to-lean mass ratios to prevent sarcopenic lean mass wasting.