This Study Investigates β-hydroxy-β-methylbutyrate (HMB) and 2-hydroxybenzylamine (2-HOBA), When Administered Either Individually or in Combination Contributes to an Increased Quality of Health, Specifically Improving Muscular Strength and Cognitive Functioning in Adults Over the Age of 65.

While the concept of using food or food components for medicinal purposes dates back many years ago, the term "nutraceuticals" is gaining respect in present day. Nutraceuticals are described as products that are derived from food sources which provide additional health benefits, include HMB, 2-HOBA, omega-3 fatty acids, probiotics, and antioxidants. These substances show considerable promise in extending health span (period of life spent in good health)through their ability to target aging hallmarks, protect against chronic diseases and enhance cellular resilience.

HMB is a naturally produced substance that is made when the body breaks down an amino acid called leucine, one of the building blocks of protein, which may promote muscle growth. Muscles are made of proteins that are continuously built up and broken down as they are used. When we exercise, we build more muscle proteins than we breakdown, and over time our muscles grow bigger and stronger. When we do not use our muscles (e.g., sedentary behavior), our muscles get smaller and weaker.

This fatty acid occurs in limited quantities within the human body, as only \~5% of dietary leucine converts to HMB. Healthy individuals typically produce 0.2- 0.4 g of HMB per day through normal metabolism.

2-HOBA also known as salicylamine, is a natural substance found in plants such as Himalayan buckwheat. It has demonstrated a reputation that helps protect your cells from damage caused by stress and aging. It may help protect your brain, keep your heart healthy and slow down aging-related damage.

The use of this product is considered experimental, and we may not know all the risks associated with it as yet, but that Health Canada has not objected to its use in this study. Both products are approved by Health Canada separately but no study has been examined the combination of both.

• β-Hydroxy-β-methylbutyrate (Dietary supplement), also known as HMB (H): Participants in intervention group HMB (H) will receive HMB supplementation at a dose of 3g/day, consisting of 2 tablets of 750mg each, twice daily for a period of 90 days.
• 2-hydroxybenzylamine (Dietary supplement), also known as 2-HOBA (2-H): Participants in the intervention group (2-H) will receive 2-HOBA at a dose of 650mg/day, respectively consisting of 2 tablets of 162.5mg each, twice daily for a period of 90 days.
• β-Hydroxy-β-methylbutyrate and 2-hydroxybenzylamine (Dietary supplement), also known as HMB (H) and 2-HOBA (2-H): Participants in the intervention group (H-2-H) will receive HMB + 2-HOBA at a dose of 3g and 650 mg/day, respectively, consisting of 2 tablets of 750mg and 325mg each, twice daily for a period of 90 days.
• Placebo (Dietary supplement), also known as Control: Participants in control group (c) will receive 2 tablets- twice daily, each containing the same ingredients, placebo will be identical color and weight matched tablets with excipients (no HMB and no 2-HOBA) for a period of 90 days.

Primary outcomes

• Effect of 90 days of HMB and/or 2-HOBA supplements when administered either individually or in combination on muscle mass. [12 weeks]: Characterize changes in total muscle mass using D3 creatine stable isotope technique before and after 90 days of supplements.

Secondary outcomes

• Effect of 90 days of HMB and/or 2-HOBA supplements when administered either individually or in combination on cardiorespiratory fitness levels (Vo2peak). [12 weeks]: Characterize changes in cardiorespiratory fitness levels (Vo2peak), using an indirect calorimeter, before and after 90 days of supplements.
• Effect of 90 days of HMB and/or 2-HOBA supplements, when administered either individually or in combination, on immune function. [12 weeks]: Characterize changes in immune function including neutrophil/lymphocyte and response to immune challenge, before and after 90 days of supplements
• Effect of 90 days of HMB and/or 2-HOBA supplements when administered either individually or in combination on cognitive function using the CANTAB cognitive tools. [12 weeks]: Characterize changes in cognitive function including attention using memory, executive function, reaction time and delayed match sample testings, before and after 90 days of supplements.
• Effect of 90 days of HMB and/or 2-HOBA supplements when administered either individually or in combination on muscle strength. [12 weeks]: Lower limb muscle strength will be assessed using a biodex dynamometer in older adults before and after 90 days of supplements
• Effect of 90 days of HMB and/or 2-HOBA supplements, when administered either individually or in combination, on inflammatory markers. [12 weeks]: Characterize changes on inflammatory markers including IL-6, TNF-alpha, CRP before and after 90 days of supplementation.

Sex: All, ages: 65 Years to any, accepts healthy volunteers

Inclusion Criteria:

•. 65 years of age

* English or French speaking
* Females not of childbearing potential
* Willing to maintain current lifestyle and dietary habits, including level of physical activity, allowed medication/supplements habits for the duration of the study

Exclusion Criteria:

* Known cardiac diseases, known arterial fibrillation, hepatic diseases, immune diseases (e.g. Individuals with an acute infectious disease, autoimmune disease or are immune compromised), ulcers, asthma, gout, severe anemia, hay fever, nasal polyps.

  * Chronic kidney disease \[estimated glomerular filtration rate (GFR) < 35 mL/min\].
  * Neurological injury/disorder with significant persistent neurological or functional deficit (e.g., stroke with hemiparesis, spinal cord injury, muscular dystrophy, myopathy, myasthenia gravis, Parkinson's disease, peripheral polyneuropathy).
  * Neuropsychological condition and/or cognitive impairment that, in the QI's opinion, could interfere with study participation
  * History of confirmed chronic obstructive pulmonary disease with a severity grade > 2 on the Medical Research Council Dyspnea Scale.
  * Uncontrolled hypothyroidism or hyperthyroidism. Hypothyroid patients who have changed their dose of hormone replacement therapy in the 6 weeks before screening are not eligible.
  * Underlying muscle diseases, including a history of or currently active myopathy (e.g., dermatomyositis, polymyositis, etc.) or muscular dystrophies.
  * Confirmed rheumatoid arthritis, acquired immunodeficiency syndrome (AIDS), type 1 or type 2 diabetes mellitus.
  * History of cancer in the last 6 months.
  * Not on any medications including NHPs/living with medical conditions that would compromise the study outcome or the safety of the research participant.
  * Known allergy to study medication or its components (non-medicinal ingredients).
  * Allergy to aspirin/salicylate or if using other drugs containing acetylsalicylic acid or other salicylates and a history of ASA-sensitive asthma/bronchospasm

The following list of medications/NHPs will be excluded (and weaned as seen necessary by the study physician) prior to and during the study:

* Participants on newly initiated cholesterol-lowering medication will be excluded. Those on stable regimens for ≥3 months will be included and will be monitored for potential interactions as per the HMB monograph.
* Medications associated with muscle weakness or immune effects (i.e., oral glucocorticoids).
* Medications or supplements affecting skeletal muscle metabolism or weight including: Use of MAO-I's (monoamine oxidase inhibitors), additional consumption of 2-HOBA, Vitamin D or HMB, anabolic steroids, selective androgen receptor modulators (SARMs), corticosteroids, GLP-1s, or other weight loss medications).
* Excessive protein supplementation (i.e., >2.0 g/kg/day).
* All participants must be on a stable dose of allowed supplements/medications for at least 3 months prior to enrollment. All concomitant therapies will be documented.

Non-pharmacological interventions that could influence study outcomes (e.g., pulmonary rehabilitation, structured exercise programs) will not be permitted.

Participants undergoing such therapies will be excluded. Any new interventions started during the study must be reported and if judged inappropriate, will result in withdrawal from the trial.

• Gustavo Duque, Medical Doctor, Principal investigator, McGilll University Health Centre