This clinical study, designed as a double-blind, randomized, placebo-controlled trial, aims to investigate the potential of nicotinamide riboside (NR) to decelerate functional decline in the elderly frail population. In animal studies, NR, which is converted to nicotinamide adenine dinucleotide (NAD), has shown potential as a neuroprotective agent, with indications of protection against amyotrophic lateral sclerosis (ALS), Alzheimer's dementia, and Parkinson's disease. Furthermore, aging is commonly associated with decreased tissue NAD levels, a phenomenon linked to premature aging and a spectrum of age-related disorders, including cardiovascular diseases and cancers. Existing preclinical and clinical research highlights the promise of NAD replenishment through enhanced DNA repair, sirtuin activity, and improved mitochondrial function. The research center has conducted two phase II clinical trials on NR for Parkinson's disease (NAD-PARK and NR-SAFE), administering up to 3000 mg of NR daily. These trials have shown promising results, indicating NR's potential as a treatment that may alter the course of the disease and possibly as neuroprotective treatment in Parkinson's disease.

The NAD age trial primarily aims to determine:

• The efficacy of NAD therapy in improving clinical symptoms of frailty, evaluated through standardized physical and cognitive function tests.
• The safety of administering 2000 mg NR daily in an elderly frail population.

The study will include 100 individuals, classified as frail based on the Fried Frailty Phenotype. Participants will be randomly assigned to receive either 2000 mg of NR daily or a placebo. Over a 52-week period, participants will undergo:

• Clinical evaluations, including actigraphy and questionnaires.
• Cognitive assessments.
• Bio sampling.
• Magnetic resonance imaging (MRI).
• Positron emission tomography (FDG-PET) scanning.

The outcomes of this study could potentially demonstrate that NR effectively reduces signs of frailty, offering considerable advantages to the individuals affected, their families, and society as a whole.

This study aims to administer 2000 mg of nicotinamide riboside (NR) daily to explore its effects on brain and body metabolism in an elderly, frail population. The research design is a single-center, double-blind, randomized, placebo-controlled approach. Participants will be evenly randomized into two groups in a 1:1 ratio: one to receive a placebo and the other to receive 2000 mg of NR daily. The intervention will last for 52 weeks, during which primary and secondary outcomes will be assessed across and within both groups.

The primary objective is to evaluate the impact of NR on gait speed by comparing the treatment group with the placebo group. Secondary objectives include assessing the safety and tolerability of NR, as well as its clinical effects on physical and cognitive functions, using standardized tests. Furthermore, exploratory objectives will be pursued using various methods such as questionnaires, biosampling, actigraphy, and brain scans. These scans will include 31P-MR-spectrometry to analyze NAD levels in the brain and FDG-PET to assess metabolic network activity. The study will include 100 frail individuals who have provided informed consent. Biological samples to be collected include blood/serum, blood cells, urine, and fecal samples.

Given the previously demonstrated potential of NR in reducing symptoms of Parkinson's disease, this study seeks to expand knowledge of its effects on an elderly, frail population without neurodegenerative disorders. If NR is found to be effective in improving measures of frailty, it could significantly impact societal health and economy, especially considering the extensive socio-economic challenges associated with frailty.

Inclusion Criteria:

• Participant must understand the nature of the study and be able to provide written, informed consent.
• Male or female aged ≥ 75 years at baseline.
• Fried Frailty Phenotype score ≥ 3 to identify frail individuals.
• Montreal Cognitive Assessment (MoCA) at screening adjusted to age, gender, and educational level, with a threshold set at the 10th percentile (z-score ≤ -1.28).

Exclusion Criteria:

• Inability to provide informed consent.
• Does not reside in a facility or institution.
• Advanced disability, end-stage disease, presence of severe chronic illness and/or life expectancy of less than a year.
• Inability to complete a 6-minute walk test (6MWT) and/or contraindications to the procedure (history of unstable angina or myocardial infarction within 30 days prior to the test).
• Diagnosis of active malignancy in the last 2 years at baseline (exceptions include non-metastatic skin conditions and non-metastatic and/or treated prostate cancer with stable prostate-specific antigen (PSA) levels in six months prior to baseline). Specific considerations may apply depending on the type of cancer.
• Significant neurological or psychiatric disorders, including but not limited to psychotic disorders, severe bipolar or unipolar depression, multiple sclerosis, uncontrolled seizure conditions, and neurodegenerative disorder.
• A history of cerebrovascular events, excluding transient ischemic attack (TIA) that occurs more than 3 months prior to baseline.
• Hospitalization or major surgery within 3 months prior to baseline.
• Significant changes in medications or treatment plans made less than one month prior to baseline, judged by the site investigator to interfere with the subject's participation in the study.
• Consumption of NAD precursor supplements (e.g., Nicotinamide riboside, nicotinamide mononucleotide or Vitamin B3), or related supplements within 6 months prior to baseline.
• Elective surgeries scheduled during the study duration.
• Concurrent participation in other clinical trials with interventions that could affect frailty measures.
• Any medical history, at the discretion of the investigator, might hinder compliance with study procedures or increase risk to the participant.

Participants and all care providers and investigators are blinded during the trial and during data analysis.