What are the guidelines for a medical workup and treatment in anti-aging medicine?

Anti-Aging Medicine Guidelines and Workup

Core Assessment Framework

The foundation of anti-aging medicine workup centers on frailty assessment using validated instruments, followed by comprehensive geriatric assessment (GA) targeting modifiable aging mechanisms, rather than treating aging itself as a disease. 1

Initial Screening and Risk Stratification

• Use a validated frailty index (FI) or frailty phenotype assessment as the primary screening tool to grade biological age and risk, as frailty degree correlates directly with mortality and morbidity outcomes 1
• The frailty index should assess accumulation of health-related deficits across multiple domains, recognizing that everyone accumulates these deficits with age but at heterogeneous rates 1
• Frailty states are dynamic and bidirectional—those with pre-frailty can transition back to robust status, making early intervention critical 1

Comprehensive Geriatric Assessment Domains

Perform GA across seven high-priority domains, as this approach has been validated to predict adverse outcomes and guide interventions: 1

1. Physical Function Assessment:

   • Document falls in the past 6 months (≥1 fall indicates impairment) 1
   • Measure 4-meter gait speed (≥4 seconds or ≤1.0 m/s indicates impairment) 1
   • Assess ability to walk one block and climb one flight of stairs 1

2. Functional Status:

   • Evaluate instrumental activities of daily living (IADLs): walking, transportation, meals, housework, medication management, financial management 1
   • Assess basic activities of daily living (ADLs): transferring in/out of bed, dressing, bathing 1
   • Any limitation requiring assistance indicates functional impairment requiring intervention 1

3. Cognitive Function:

   • Screen for cognitive impairment using validated tools 1
   • Assess for dementia, as this significantly impacts treatment decisions and care planning 1

4. Emotional Health:

   • Screen for depression and anxiety 1
   • Distinguish between psychiatric disease requiring treatment versus conscious relinquishment of will to live in frail elderly 1

5. Comorbidity Assessment:

   • Document all chronic conditions affecting physiologic reserve 1
   • Calculate comorbidity burden as it directly impacts pharmacokinetics and pharmacodynamics 1

6. Polypharmacy Evaluation:

   • Review all medications including over-the-counter, vitamins, supplements, and herbal preparations 1
   • Identify inappropriate polypharmacy—the use of potentially excessive or inappropriate medications 1
   • Consider de-prescribing as a viable anti-aging strategy, as polypharmacy increases frailty scores 2
   • Adjust dosing for age-related changes in renal function using CKD-EPI creatinine-cystatin C equation, which is more accurate than creatinine-based equations alone in older adults 1

7. Nutritional Status and Social Support:

   • Assess for malnutrition risk, as older persons are at special risk due to multiple factors 1
   • Evaluate social support networks 1

Laboratory and Biomarker Assessment

Measure cellular senescence markers when evaluating biological aging: 1

• Primary markers: p16 and/or p21 expression (cell cycle arrest proteins) 1
• Auxiliary markers (use at least two): 1
  • LMNB1 (lamin B1) levels
  • DNA damage markers
  • Senescence-associated secretory phenotype (SASP) factors
  • Advanced glycation end products (AGEs) accumulation 1
  • Oxidative damage markers 1

Assess cardiovascular and metabolic parameters:

• Evaluate for subcellular damage including collagen deposition, calcium channel expression changes, and mitochondrial dysfunction 1
• Screen for AGE accumulation, which reduces blood supply in skeletal muscle leading to sarcopenia 1

Organ-Specific Considerations

Cardiovascular Assessment:

• Age-related changes include decreased cardiac reserve, decreased LV compliance, increased arterial stiffness, and degeneration of sinoatrial/atrioventricular nodal function 1
• These changes increase susceptibility to heart failure, bradycardia, AV block, and orthostatic hypotension with standard medications 1

Musculoskeletal Evaluation:

• Assess for sarcopenia through physical performance testing 1
• AGE accumulation in skeletal muscle correlates with functional impairment and high frailty scores 1

Evidence-Based Interventions

Lifestyle Modifications (First-Line)

Implement dietary interventions targeting nutrient-sensing pathways: 2, 3

• Calorie restriction is the most well-established longevity intervention, reducing frailty in mice and nonhuman primates 2
• Intermittent fasting reduces frailty markers, though effects are more pronounced in males 2
• Protein restriction, particularly methionine limitation, reduces mTOR activation and extends lifespan in rodent models 2
• Reduce dietary AGE intake by avoiding high-temperature cooking methods and processed foods 1
• Consider herbal teas containing polyphenols (apigenin, luteolin, kaempferol) that inhibit AGE formation 1

Exercise prescription: 2

• Regular aerobic exercise and high-intensity interval training consistently reduce frailty in animal models 2
• Voluntary physical activity improves physical performance and reverses frailty phenotypes 2
• Combine exercise with other interventions for synergistic effects 2

Pharmacological Interventions

Consider evidence-based pharmaceutical approaches: 2, 4, 3

• mTOR inhibitors (e.g., rapamycin) extend healthspan and reduce frailty indices by targeting nutrient-sensing pathways 2
• Senolytics that eliminate senescent cells are emerging as promising interventions with human trials underway 1, 2, 4
• Autophagy enhancers show promise in preclinical studies for maintaining health during aging 4

Supplements with evidence: 2, 4

• Resveratrol reduces frailty in naturally aging mice 2, 4
• Alpha-ketoglutarate attenuates frailty in aging mice 2
• Curcumin shows promise with minimal side effects 4
• Urolithin A modulates autophagy, induces mitophagy, and improves mitochondrial gene expression in elderly individuals, though it should not replace guideline-directed therapy for established cardiovascular disease 5

Multidisciplinary Interventions Based on GA Results

When functional impairments are identified: 1

• Physical therapy referral for gait evaluation, assistive device assessment, lower-extremity strengthening, and balance training 1
• Occupational therapy for home safety evaluation and functional impairment treatment 1
• Nutritional support when malnutrition risk is identified 1
• Social work referral for inadequate social support 1

Integrated care approach: 1

• Coordinate efficient, person-centered care responding to health and social needs 1
• Community-based integrated care interventions significantly improve physical function and frailty 1

Treatment Modification Principles

Adjust interventions based on frailty degree: 1

• For patients with functional impairment in non-curative settings: 1
  • Consider single-agent rather than combination therapy
  • Modify dosage (e.g., 20% dose reduction with escalation as tolerated)
  • Modify treatment schedule if appropriate
  • Implement more frequent toxicity monitoring (weekly or biweekly)

Pharmacodynamic considerations in aging: 1

• Decreased baroreceptor sensitivity increases orthostatic hypotension risk with antihypertensives 1
• Down-regulation of beta-adrenergic receptors alters drug responses 1
• Increased arterial stiffness increases hemodynamic lability risk from vasodilators 1

Critical Pitfalls and Caveats

Sex-specific effects: 2

• Many longevity interventions show differential effects between males and females 2
• High-fat diet increased frailty only in male mice despite weight gain in both sexes 1

Timing considerations: 1, 2

• After age 65, frailty development accelerates at approximately twice the rate of younger individuals 1
• Some interventions show greater benefits when started earlier, while others remain effective when initiated later 2

Extrapolation limitations: 2

• Translating animal model findings to humans requires caution due to different lifespans and physiological responses 2
• Computational models embracing aging complexity will facilitate translation from cellular/animal models to human medicine 1

Realistic expectations: 6

• Aging is not a disease but a process—focus on health maintenance rather than illusory "anti-aging" cures 6
• Addressing only one disease of aging would add approximately 2.87 years to average lifespan; combination approaches are necessary 2

Senolytic therapy considerations: 1

• Senescent cells show pleiotropism and heterogeneity within different organs and timeframes 7
• Extensive testing is required given the complexity of targeted senescent cell populations 7

Monitoring and Reassessment

Repeat frailty assessment at regular intervals: 1

• Frailty degree should be reassessed to track intervention effectiveness 1
• Improved frailty scores confer the same mortality risk as those who remained robust/pre-frail 1

Verify intervention effects: 1

• Confirm that interventions reduced senescent cell abundance or activity 1
• Document coincident changes in pathophysiological phenotypes 1

Report outcomes transparently: 1

• Document both positive and negative results 1
• Report situations where interventions did not work and possible reasons 1