Population ageing is reshaping health systems worldwide. The number of people aged 60 years and older is expected to rise from about 1 billion in 2020 to 2.1 billion by 2050, with nearly two-thirds living in low- and middle-income countries.[1] This transition is accompanied by increasing multimorbidity, frailty, sarcopenia, cognitive impairment, malnutrition, polypharmacy and functional dependence.

More than half of adults older than 60 years have multimorbidity, while frailty prevalence varies by assessment method.[2,3] Polypharmacy further increases drug interactions, prescribing cascades, treatment burden and medication-related harm.[4] These factors interact to determine whether an older adult remains resilient or deteriorates disproportionately after infection, dehydration, surgery, medication changes or hospitalisation.

Disease-centred care remains essential but may inadequately address physiological reserve, cognition, mobility, nutrition, caregiver capacity and personal priorities. Older adults with similar ages and diagnoses may differ markedly in treatment tolerance and recovery potential.

The World Health Organization’s healthy-ageing framework defines later-life health through functional ability and intrinsic capacity rather than disease absence alone.[5,6] Intrinsic capacity includes locomotor, cognitive, psychological, sensory and vitality domains, whose decline may precede overt organ failure.

Frailty is a major clinical expression of reduced reserve. The Fried phenotype identifies frailty through weight loss, exhaustion, weakness, slow gait and low physical activity,[7] while the deficit-accumulation model measures cumulative symptoms, diseases and disabilities.[8] Both approaches predict falls, hospitalisation, disability, institutionalisation and mortality.

Biological ageing underlies this vulnerability through genomic instability, mitochondrial dysfunction, impaired proteostasis, cellular senescence, altered communication and chronic inflammation.[9] Clinical deterioration may consequently present as delirium, immobility, falls, anorexia or functional dependence rather than isolated organ failure.

This review proposes the Multisystem Vulnerability Cascade as an integrative precision-geriatric framework describing progressive multisystem reserve erosion and impaired recovery after stressor exposure. It links biological ageing, frailty, sarcopenia, intrinsic-capacity decline, multimorbidity, polypharmacy, cognition, nutrition, social context and digital monitoring.

The review aims to define the cascade, integrate its major domains, map validated assessment tools and outline practical person-centred applications, including for India and other resource-constrained settings.

2. Search Strategy and Evidence Acquisition

This article was developed as a structured narrative and conceptual review. A formal systematic review or meta-analysis was not performed because the aim was to integrate evidence across several related fields rather than address a narrowly defined diagnostic or therapeutic question. The review was guided by the Scale for the Assessment of Narrative Review Articles and principles of transparent search reporting.[10,11]

Targeted searches were conducted in PubMed/MEDLINE, Google Scholar, publisher databases, guideline repositories and institutional websites. Search domains included biological ageing, inflammaging, immunosenescence, frailty, sarcopenia, intrinsic capacity, multimorbidity, organ reserve, polypharmacy, comprehensive geriatric assessment, digital health, artificial intelligence and ageing in India and other low- and middle-income countries.

Priority was given to systematic reviews, meta-analyses, longitudinal and population-based studies, consensus statements, guidelines, official public-health documents and validation studies of established geriatric instruments. Foundational older sources were retained when they introduced concepts or tools still used in practice.

Numerical estimates, thresholds and scoring criteria were included only when directly supported by cited sources. Where findings varied by population, setting or method, source-specific values were reported rather than treated as universal.

Unverifiable, duplicative, superseded, predatory or opinion-based sources were excluded. Abstract-only evidence was not used for major clinical or numerical claims when full-text or authoritative material was required. Citation tracking and reference lists identified additional relevant studies.

Evidence was synthesised through domain mapping across biological ageing, frailty, sarcopenia, intrinsic capacity, multimorbidity, cognition, nutrition, mobility, medication burden, social vulnerability and digital health.

The proposed cascade is therefore an integrative conceptual framework derived from converging evidence and is not presented as a validated diagnostic syndrome or clinical prediction tool.

3. From Disease-Centred Medicine to Geriatric Network Medicine

Disease-centred medicine has improved management of individual conditions but becomes difficult when multiple guidelines are applied simultaneously to older adults with multimorbidity, frailty, cognitive impairment and polypharmacy.

Boyd et al. demonstrated this by applying disease-specific guidelines to a hypothetical 79-year-old woman with five chronic conditions, resulting in 12 medications and a complex non-pharmacological regimen.[12] Individually appropriate recommendations may therefore become collectively burdensome, hazardous or inconsistent with patient priorities.

Multimorbidity should be viewed as an interacting clinical network rather than a simple disease count. Outcomes depend on disease severity, organ involvement, cognition, mobility, nutrition, treatment burden, social support and prognosis. The American Geriatrics Society recommends incorporating patient preferences, expected benefit, competing risks, feasibility and treatment burden,[13] while NICE emphasises reducing polypharmacy, fragmented care and unnecessary treatment through shared decision-making.[14]

Network medicine supports this approach by recognising that disease phenotypes arise from disturbances across interconnected biological systems.[15] In older adults, diabetes, kidney disease, heart failure, depression, cognitive impairment and sarcopenia may interact through inflammation, vascular dysfunction, altered drug handling, immobility and malnutrition.

The Ariadne principles promote assessment of disease interactions, realistic goal setting, individualised management and planned reassessment.[16] Similarly, the Age-Friendly Health Systems 4Ms—What Matters, Medication, Mentation and Mobility—identify interdependent intervention domains.[17]

This approach does not reject disease-specific treatment. Instead, it places it within a broader geriatric framework incorporating frailty, intrinsic capacity, cognition, nutrition, prognosis, medication burden and personal goals. The objective shifts from maximising isolated disease targets to preserving function, resilience, safety and quality of life.

4. Defining the Multisystem Vulnerability Cascade

The Multisystem Vulnerability Cascade is a conceptual framework describing progressive loss of multisystem reserve in older adults. It is not a new disease, validated score or replacement for frailty and multimorbidity. Unlike acute multiorgan dysfunction syndrome, it begins with declining reserve and impaired recovery rather than overt organ failure.

The framework builds on geriatric syndromes such as delirium, falls, incontinence and functional decline, which arise from shared vulnerabilities including cognitive impairment, reduced mobility and baseline functional limitation rather than a single organ-specific disease.[18]

Frailty provides the main clinical expression of this vulnerability and reflects reduced ability to restore homeostasis after stress, increasing the risk of delirium, falls, disability and death.[19] Consequently, minor events such as infection, dehydration, medication changes or brief hospitalisation may cause persistent decline.

Frailty reflects cumulative dysregulation across multiple physiological systems, with combined abnormalities being more informative than any single deficit.[20] Physical resilience—the ability to resist or recover after stress—represents its dynamic counterpart.[21]

The cascade comprises five interacting levels:

1. Biological vulnerability: ageing mechanisms, senescence, mitochondrial dysfunction and chronic inflammation.
2. Reserve erosion: reduced muscular, cognitive, nutritional, immune, renal and cardiovascular adaptability.
3. Measurable vulnerability: frailty, sarcopenia, intrinsic-capacity decline, multimorbidity, cognitive impairment and medication burden.
4. Stressor exposure: infection, surgery, dehydration, hospitalisation, medication change, falls or social disruption.
5. Cascade outcomes: delirium, functional decline, disability, institutionalisation or death.

These levels are descriptive and do not constitute a validated staging system. Hospitalisation and restricted activity may shift older adults from independence to disability, particularly in the presence of frailty.[22] Recovery may remain incomplete when disability persists at discharge.[23] Such events can also create feedback loops by worsening mobility, nutrition, cognition and medication burden, thereby increasing future vulnerability.

The cascade extends beyond multimorbidity because disease count alone does not capture reserve or function. It is also broader than frailty, incorporating biological ageing, disease interactions, medication-related harm, social vulnerability and stressor-related outcomes.

Its defining feature is interaction. Multimorbidity increases medication exposure; renal impairment increases drug toxicity; sedative and anticholinergic burden impair cognition and mobility; sarcopenia increases falls risk; and social isolation delays illness recognition. Together, these factors may convert compensated vulnerability into decompensation.

The Multisystem Vulnerability Cascade may therefore be defined as a chronic, dynamic and potentially modifiable trajectory in which biological ageing and multisystem reserve erosion interact with frailty, sarcopenia, multimorbidity, polypharmacy, intrinsic-capacity decline and social vulnerability, producing disproportionate functional, cognitive or physiological deterioration after stressor exposure.

5. Biological Ageing, Inflammation aging and Immunosenescence

The cascade begins with biological ageing, which progressively reduces tissue and organ-system capacity to maintain homeostasis. Unlike chronological age, biological ageing reflects cumulative molecular, cellular and physiological changes that determine reserve, resilience and recovery. Older adults of the same age may therefore differ substantially in strength, cognition, immune competence, renal reserve and tolerance of illness or medication.

The hallmarks-of-ageing framework explains this vulnerability through interacting mechanisms including genomic instability, epigenetic alteration, impaired proteostasis and autophagy, mitochondrial dysfunction, cellular senescence, stem-cell exhaustion, chronic inflammation and dysbiosis.[24,25] These processes converge across organ systems, lowering the threshold at which minor stressors produce clinically important decline.

Loss of resilience is a major clinical expression of ageing. While robust adults may recover after infection, dehydration, surgery or medication changes, vulnerable older adults may develop delirium, anorexia, immobility or persistent functional loss. Biological ageing is therefore reflected not only by biomarkers but also by delayed or incomplete recovery.

Biological age may be estimated using epigenetic, transcriptomic, proteomic, metabolomic and composite clinical measures.[26] DNA-methylation clocks demonstrate that biological age may differ from chronological age and correlate with morbidity, disability and mortality.[27–29] However, these remain mainly research tools and should not replace clinical assessment of frailty, mobility, cognition, nutrition and functional trajectory.

Inflammaging and immunosenescence connect ageing biology with clinical vulnerability. Inflammaging refers to persistent low-grade inflammatory activation, while immunosenescence describes age-related remodelling of innate and adaptive immunity.[30–32] Together, they may cause impaired infection defence and poorly regulated inflammatory responses.

Contributors include cellular senescence, mitochondrial dysfunction, chronic infection, visceral adiposity, altered gut permeability and inflammasome activation.[31] Consequences include endothelial dysfunction, insulin resistance, muscle catabolism, impaired tissue repair and reduced resilience. Thymic involution, reduced naïve T-cell production and altered B-cell function also increase infection susceptibility, reduce vaccine responsiveness and contribute to atypical illness presentation.[32,33]

Inflammatory markers such as C-reactive protein and interleukin-6 are often higher in frail and pre-frail adults, but their limited specificity prevents diagnostic use.[34] They should therefore complement, rather than replace, validated clinical measures.

Inflammation also interacts with sarcopenia and multimorbidity. Chronic inflammatory signalling promotes muscle loss and metabolic dysfunction, while inactivity, obesity, kidney disease, malnutrition and recurrent illness further amplify inflammation, creating feedback loops that drive decompensation.

Inflammaging varies across populations.[35] This is particularly relevant to India and other low- and middle-income countries, where infection exposure, nutrition, pollution, adiposity, activity and socioeconomic conditions differ from high-income populations.

The clinical implication is not routine inflammatory testing but preservation of reserve through vaccination, resistance exercise, adequate nutrition, infection prevention, oral health, metabolic control, sleep optimisation and reduction of high-risk medication exposure.

Biological ageing, inflammaging and immunosenescence therefore form the upstream substrate of the cascade, becoming clinically evident through frailty, sarcopenia and declining intrinsic capacity.

6. Frailty, Sarcopenia and Intrinsic-Capacity Decline

Frailty, sarcopenia and intrinsic-capacity decline are related but distinct manifestations of reduced multisystem reserve. Frailty reflects vulnerability to poor recovery after stress, sarcopenia denotes impaired skeletal-muscle function, and intrinsic capacity represents the physical and mental abilities required to maintain function. Together, they link biological ageing with clinical decompensation.

Frailty is a dynamic state rather than a fixed diagnosis. The Fried phenotype defines frailty by weight loss, exhaustion, weakness, slow gait and low activity; three or more criteria indicate frailty and one or two indicate pre-frailty.[7] The deficit-accumulation model quantifies the cumulative burden of diseases, symptoms, impairments and disabilities.[8] Although they identify partly different populations, both predict adverse outcomes and reduced recovery capacity.

Frailty prevalence varies with the assessment method and is generally higher with deficit-based approaches.[3] Pre-frail adults have a substantially greater risk of developing frailty than robust individuals, making pre-frailty an important opportunity for prevention.[36] Frailty may improve with exercise, rehabilitation, nutritional support, medication optimisation and recovery from acute illness.

Sarcopenia is a major contributor to physical frailty and loss of independence. European criteria define low muscle strength as probable sarcopenia, additional low muscle mass as confirmed sarcopenia and impaired physical performance as severe sarcopenia.[37] Suggested thresholds include grip strength below 27 kg in men or 16 kg in women, gait speed ≤0.8 m/s and a Short Physical Performance Battery score ≤8.[37]

Asian criteria recommend grip strength below 28 kg in men and 18 kg in women, gait speed below 1.0 m/s and chair-rise time ≥12 seconds.[38] These may be more relevant to Asian populations, although further Indian validation is required. Regardless of the threshold, reduced strength and slow gait indicate clinically important loss of locomotor reserve.

Frailty and sarcopenia should not be considered synonymous. Muscle loss may dominate in one patient, while cognitive impairment, malnutrition, multimorbidity or medication burden may be more important in another. Intervention should therefore target the principal mechanism of decline.

The World Health Organization defines intrinsic capacity across locomotor, cognitive, vitality, sensory and psychological domains.[39] The Integrated Care for Older People framework aims to identify deterioration in these areas before irreversible disability develops.

Measurement remains heterogeneous. Gait and chair-rise tests assess locomotion, grip strength and nutrition reflect vitality, brief cognitive tools assess cognition, and depression scales evaluate psychological capacity.[40] As no universal composite score exists, intrinsic capacity is best used as a structured multidomain framework.

Decline in one or more intrinsic-capacity domains is common among community-dwelling older adults and predicts later functional deterioration and mortality.[41,42] Intrinsic capacity and frailty are complementary: the former supports early detection, while the latter identifies more advanced vulnerability to stressors.[43]

Within the cascade, early decline may present as weaker grip, slower gait, weight loss, sensory impairment, depression or cognitive slowing. Intermediate stages include pre-frailty, probable sarcopenia and multidomain intrinsic-capacity loss, while advanced vulnerability includes established frailty, severe sarcopenia, delirium susceptibility, recurrent hospitalisation and dependence.

Assessment should combine frailty, muscle function, intrinsic-capacity domains, cognition, nutrition, medication burden and functional trajectory. The aim is not to accumulate scores, but to identify modifiable drivers and intervene before stressor exposure produces irreversible disability.

Table 1. Frailty, Sarcopenia and Intrinsic Capacity within the Cascade

7. Multimorbidity, Polypharmacy and Organ-Reserve Erosion

Frailty and sarcopenia become more clinically significant when accompanied by multimorbidity and polypharmacy. Although multimorbidity is commonly defined as two or more chronic conditions, vulnerability depends more on disease severity, organ-system involvement and functional impact than on disease count alone.[44]

Common clusters include cardiometabolic, neuropsychiatric, musculoskeletal and respiratory disorders.[45] These reduce vascular, cognitive, mobility and recovery reserve through different pathways. Complex multimorbidity involving at least three conditions across three organ systems may better reflect multisystem reserve loss and is associated with disability and mortality.[46]

Individually stable diseases may collectively leave little capacity to tolerate acute stress. Infection, dehydration, medication changes or hospitalisation may therefore precipitate delirium, acute kidney injury, falls and functional decline through failure of compensation across multiple systems.

Polypharmacy, often defined as five or more medicines, is a potentially modifiable contributor.[47] However, risk depends on indication, dose, renal function, interactions, treatment burden, prognosis and tolerance rather than medicine count alone. Age-related reductions in drug clearance and increased sensitivity to sedative, anticholinergic and hypoglycaemic effects may convert minor adverse reactions into delirium, falls, bleeding or hospitalisation.

STOPP/START version 3 and the 2023 AGS Beers Criteria help identify inappropriate medicines, prescribing omissions, interactions and renal-dose problems but should support, not replace, clinical judgement.[48,49] A prescribing cascade occurs when an adverse drug reaction is mistaken for a new illness and treated with another medicine.[50] New confusion, dizziness, oedema, constipation, falls or weakness should therefore prompt medication review.

Serious adverse events commonly involve anticoagulants, insulin, antiplatelet agents and glucose-lowering drugs.[51] Medication safety requires monitoring, dose adjustment, patient education and careful transitions of care.

Deprescribing is the supervised reduction or withdrawal of medicines whose harms, burden or limited benefit outweigh their value.[52] Its goal is the safest and simplest effective regimen aligned with prognosis, function and patient priorities.

A cascade-oriented review should confirm current indications, expected time to benefit, possible drug-related symptoms, renal dosing, interactions, prescribing omissions and opportunities for simplification. Multimorbidity and polypharmacy should therefore be assessed together because therapeutic complexity may convert compensated reserve loss into multisystem decompensation.

Table 2. Multimorbidity and Medication-Related Cascade Pathways

8. Precision Geriatric Care Framework

The proposed Precision Geriatric Care Framework translates the cascade into a practical pathway without replacing comprehensive geriatric assessment, frailty or sarcopenia evaluation, intrinsic-capacity screening or medication review. It organises these approaches around three questions:

1. Which reserves have declined?
2. Which stressor may precipitate deterioration?
3. Which modifiable factor can be addressed now?

Precision geriatric care extends beyond biomarker-based medicine by integrating biological vulnerability, frailty, cognition, mobility, nutrition, multimorbidity, medication burden, social support, environment and personal goals. A treatment may achieve a disease-specific target yet remain inappropriate if it increases falls, delirium, anorexia, dependence or treatment burden.

The framework begins with baseline vulnerability mapping, including frailty, mobility, nutrition, cognition, ADL/IADL function, falls, medication exposure, sensory impairment, social support and recent healthcare use. Grip strength, formal sarcopenia assessment, CIRS-G and detailed cognitive testing may be added in specialist settings.

The second step is stressor anticipation. Common triggers include infection, dehydration, surgery, hospitalisation, immobilisation, hypoglycaemia, orthostatic hypotension, medication changes, bereavement and caregiver disruption. Early identification enables preventive planning.

The third step is intervention at modifiable nodes, including resistance and balance exercise, protein-energy support, medication simplification or deprescribing, renal-dose adjustment, delirium and falls prevention, sensory correction, home-safety modification, vaccination, rehabilitation, post-discharge follow-up and caregiver support.

The fourth step is alignment with patient priorities, such as remaining at home, preserving mobility, reducing pain, avoiding hospitalisation or simplifying treatment. Patient Priorities Care suggests that goal-aligned decisions may reduce treatment burden and unnecessary healthcare use.[58]

The fifth step is longitudinal reassessment, because vulnerability changes with illness, recovery, medication exposure, rehabilitation and social circumstances. Repeated evaluation of frailty, gait, nutrition, cognition, function and medication burden is therefore more useful than a single baseline score.

Care should be adapted to vulnerability level. Robust adults require prevention and reserve maintenance; pre-frail adults need exercise, nutrition and medication optimisation; frail adults require stressor prevention, rehabilitation, safer transitions and caregiver support; and those with severe frailty or advanced illness need symptom control, reduced treatment burden and goal-concordant care.

Risk assessment should guide, not automatically restrict, treatment. High vulnerability may indicate a need for rehabilitation and close follow-up in one patient, but symptom-focused care and avoidance of burdensome interventions in another.

Comprehensive geriatric assessment remains the principal evidence-based multidomain model and is associated with a greater likelihood of older adults being alive and living at home and a lower likelihood of institutional care.[59] The cascade framework extends this approach by emphasising reserve, stressor exposure and recovery.

The pathway can be summarised as:

Map vulnerability → anticipate stressors → identify modifiable nodes → align care with patient priorities → intervene → monitor recovery and function.

This framework is intended to organise clinical reasoning rather than create a new diagnosis. Its value requires prospective validation of its effects on function, adverse outcomes and feasibility across healthcare settings.

9. Research Gaps and Future Directions

The cascade integrates established geriatric concepts, but the unified framework itself remains unvalidated. Future research should focus on five priorities.

Prospective Construct Validation

Studies should determine whether combined assessment of frailty, sarcopenia, intrinsic capacity, multimorbidity, cognition, nutrition, medication burden and social vulnerability predicts meaningful outcomes better than existing tools. Outcomes should include delirium, falls, functional decline, hospitalization, institutionalization, mortality and days alive at home.

Longitudinal Stressor–Recovery Studies

The cascade should be tested before and after defined stressors such as infection, surgery, hospitalization, medication change, dehydration or falls. Repeated assessment is needed to distinguish static risk accumulation from impaired recovery and progressive reserve loss.

Clinical Utility and Intervention Testing

Risk identification is useful only when linked to action. Pragmatic studies should test whether cascade-oriented care improves outcomes through exercise, nutritional support, deprescribing, renal-dose review, delirium prevention, falls reduction, rehabilitation and caregiver support.

Implementation, Equity and Cost

Future models must be feasible for primary care and resource-constrained settings. Research should assess acceptability, workforce requirements, training, referral pathways, digital access, cost-effectiveness and sustainability. Prediction models involving artificial intelligence should follow transparent reporting and risk-of-bias standards and undergo external validation and fairness testing [67,68].

A composite vulnerability instrument may eventually be explored, but this review does not propose variables, weights, thresholds or clinical categories. Any future model should be prospectively derived, externally validated and shown to improve decisions and outcomes before clinical use.

The research agenda should therefore progress from construct validation, to intervention testing, and finally to implementation and scaling. The framework should remain hypothesis-generating until evidence demonstrates that it adds value beyond established geriatric assessment.

Table 3. Precision Geriatric Care Framework for Cascade-Oriented Management

FIGURE1 : THE GERIATRIC MULTISYSTEM VULNERABILITY CASCADE

Table 4. Tiered Implementation of Cascade-Oriented Care in India and Other LMICs

FIGURE 2 : MULTIMORBIDITY AND MEDICATION RELATED CASCADE PATHWAYS

Figure 2. The Geriatric Multisystem Vulnerability Cascade and Key Intervention Points.

Population ageing requires care to extend beyond isolated disease management to assessment of physiological reserve, function and recovery capacity. In older adults, frailty, sarcopenia, multimorbidity, polypharmacy, cognitive vulnerability, malnutrition and social disadvantage interact across systems, making deterioration a consequence of cumulative reserve loss rather than single-organ failure. The proposed Multisystem Vulnerability Cascade links biological vulnerability, measurable decline, stressor exposure and adverse outcomes. It is not a new disease entity or validated instrument but an organising framework for understanding the interaction between reserve, stressors and recovery. Clinically, it asks which reserves are declining, which stressor may trigger deterioration and which modifiable factor can be addressed. This supports early intervention through exercise, nutrition, medication optimisation, rehabilitation, delirium and falls prevention, sensory correction, caregiver support and goal-aligned care. The framework may be especially useful in India and other low- and middle-income countries, where rapid ageing and limited specialist capacity require scalable, primary-care-based approaches. However, it remains conceptual and requires prospective validation to determine whether it improves prediction, decision-making and functional recovery beyond existing geriatric assessments. Overall, the Multisystem Vulnerability Cascade integrates ageing biology with multidomain, person-centred care to promote early recognition and prevention of potentially irreversible functional decline.

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