Effect of a Combined Exercise and Anti-Inflammatory Nutritional Intervention in Frail Older Adults

Frailty and malnutrition are prevalent, closely interconnected syndromes in older adults, associated with adverse outcomes such as functional decline, falls, institutionalization, prolonged hospitalization, and increased mortality. These conditions reinforce each other in a bidirectional cycle: malnutrition contributes to muscle loss and diminished physical function, while frailty can lead to decreased appetite and nutrient intake. Both are increasingly linked to chronic, low-grade systemic inflammation, known as "inflammaging."

Inflammaging is characterized by persistently elevated levels of circulating pro-inflammatory cytokines, such as IL-6, TNF-α, IL-8, and CRP. This inflammatory environment contributes to sarcopenia, bone demineralization, insulin resistance, and immune system decline, all of which further drive the progression of frailty. Therefore, interventions that reduce inflammaging may offer a novel therapeutic pathway to mitigate frailty and its consequences.

Multicomponent physical exercise programs-especially those incorporating strength, balance, and endurance training-have demonstrated efficacy in improving mobility and reducing inflammation in older adults. The Vivifrail© program, developed and validated for frail and pre-frail populations, offers a structured, scalable home-based exercise model. At the same time, nutritional interventions enriched with anti-inflammatory ingredients-such as extra virgin olive oil polyphenols, omega-3 fatty acids (EPA/DHA), and leucine-may support muscle anabolism and reduce systemic inflammation. Yet, despite promising evidence from each modality alone, their combined impact in frail, malnourished populations remains understudied.

The AliFrail trial addresses this gap through a randomized, controlled, open-label, two-arm clinical study conducted at the Hospital Universitario de Navarra (HUN) in Pamplona, Spain. A total of 158 community-dwelling adults aged ≥75 years with frailty and malnutrition will be randomized to receive either:

• the Vivifrail© exercise program plus a daily anti-inflammatory oral nutritional supplement (Alisenoc™), or
• the same exercise program with an isocaloric, protein-equivalent standard nutritional supplement without anti-inflammatory components.

The intervention will last 12 weeks, followed by follow-up assessments at 6 and 12 months. The primary outcome is change in physical performance measured by the Short Physical Performance Battery (SPPB). Secondary outcomes include body composition (via bioelectrical impedance), inflammatory biomarker levels (IL-6, IL-8, TNF-α, GDF-15), handgrip strength, bone health (via REMS), quality of life (EQ-5D), and major clinical outcomes (readmissions, falls, mortality). Participant adherence, safety, and adverse events will also be monitored throughout the study period.

Sample size calculation is based on detecting a 1-point difference in SPPB between groups, assuming a standard deviation of 2 points, α = 0.05, and 80% power. This requires 158 participants in total, accounting for expected loss to follow-up.

Randomization will be stratified and computer-generated, with allocation concealed using sealed opaque envelopes. Due to the nature of the intervention, the trial will be open-label for participants and clinicians, but outcome assessors will remain blinded to minimize bias. Participants will be instructed not to reveal group allocation during assessments.

Data will be recorded in secure, encrypted electronic case report forms (eCRFs). Biological samples for biomarker analysis will be stored at -80°C. Data management procedures will ensure participant confidentiality and compliance with data protection regulations.

The study has been approved by the Research Ethics Committee of Navarra (CEIm Navarra). All participants (or legal representatives) will provide informed consent prior to enrollment. The trial will be registered on a public international platform (EU Clinical Trials Register) and conducted in accordance with SPIRIT 2013 guidelines, the Declaration of Helsinki, and Good Clinical Practice (GCP) standards.

Implementation Strategy:

While the Geriatrics and Nutrition departments at HUN are not formally integrated, they will jointly collaborate on patient recruitment and assessments, coordinated from a dedicated research consultation room with nursing support. This design allows implementation without disrupting existing clinical workflows.

Barriers to implementation include limited care pathway integration, participant mobility and cognitive challenges, and logistical complexities in supplement delivery. Facilitators include strong institutional support from HUN and Navarrabiomed, a multidisciplinary research team with prior experience in similar trials, and availability of infrastructure and staff for participant support.

Significance:

AliFrail is designed to generate high-quality evidence on a personalized, combined strategy to reverse frailty through physical and nutritional intervention. Its findings could influence future clinical guidelines and healthy aging policies by supporting scalable, multimodal approaches that address the underlying biology of frailty-namely inflammaging-while enhancing physical resilience and independence in vulnerable older adults.

Inclusion criteria

• Patient aged ≥ 75 years.
• Diagnosis of frailty according to Linda Fried's criteria.
• Diagnosis of malnutrition according to GLIM (Global Leadership Initiative on Malnutrition) criteria.
• Barthel Index score ≥ 60 points.
• Absence of advanced chronic kidney disease (defined as glomerular filtration rate < 25 mL/min/1.73m²).
• Absence of terminal illness as defined by SECPAL (Spanish Society for Palliative Care) criteria.

Exclusion criteria

• Presence of type 1 or type 2 diabetes mellitus with poor metabolic control (HbA1c > 8% or insulin-dependent).
• Oropharyngeal dysphagia to liquids that prevents safe intake of oral supplementation.
• Moderate-to-severe cognitive impairment, defined as a score ≥ 5 on the Global Deterioration Scale (GDS) of Reisberg.
• Refusal to sign the informed consent by the patient, primary caregiver, or legal representative, or inability to obtain it.
• Known allergy or intolerance to any component of the study supplements.
• Institutionalized in a long-term care or residential facility.