Mitophagy and Autophagy in Elderly Subjects

Inclusion criteria

• for Active, Healthy subjects:

• >61 years of age, inclusive.
• Healthy male subjects. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis.
• Body mass index (BMI) between 15 and 32 kg/m2, inclusive.
• Able to participate and willing to give written informed consent and to comply with the study restrictions.
• Category 2 or 3 as assessed by the International Physical Activity Questionnaires (IPAQ). Activity level is ≥ 600 MET (metabolic equivalent unit) - minutes per week.
• Normal physical performance: normal gait speed, i.e. a walking ≥ 0.8 m/s in the 4-m walking test.
• Normal muscle mass: normal skeletal muscle mass index (SMI), measured by Bioimpedance analysis (BIA, ≥ 10.75 kg/m2).
• Normal muscle strength: handgrip strength (measured with the Jamar dynamometer) of ≥ 30 kg.

for Sedentary, Pre-frail subjects:

• Sedentary, pre-frail males. Pre-frailty is defined as fulfilling to at least two out of the following three criteria: low physical performance (low gait speed, i.e. a walking speed below 0.8 m/s in the 4-m walking test), low muscle mass (a low skeletal muscle mass index (SMI), measured by Bioimpedance analysis (BIA, < 10.75 kg/m2)) and/or low muscle strength: handgrip strength (measured with the Jamar dynamometer) of < 30 kg. Sedentary behaviour is defined as having an activity category of 1 as assessed by the International Physical Activity Questionnaires (IPAQ) (Activity level is ≥ 600 MET (metabolic equivalent unit) - minutes per week).
• Body mass index (BMI) between 15 and 32 kg/m2, inclusive.
• Able to participate and willing to give written informed consent and to comply with the study restrictions.
• >61 years of age, inclusive.

Exclusion criteria

• for Active, Healthy subjects:

• Presence of any contraindication to have MRI scans performed (e.g. pacemaker, intracranial clips etc.).
• Having diabetes mellitus or lower extremity peripheral vascular disease, as these conditions may interfere with interpretation of the dynamic 31P-MRS and NIRS of the lower extremity.
• Participation in a clinical trial within 90 days of screening or more than 4 times in the previous year.
• A history (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol).
• Smoking within 3 months prior to screening and inability to refrain from smoking during the course of the study (from screening to End-of-Study [EOS]).
• A history or presence of allergy to 5-aminolevulinic acid or porphyrins.
• A history or presence of allergy to lidocaine.
• Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
• Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening.
• Unwillingness or inability to refrain from consuming alcohol within 48 hours before each visit until the end of that visit.
• Unwillingness or inability to refrain from consuming 8 or more units of xanthine containing beverages and foods per day during the entire study.
• Unwillingness or inability to refrain from consuming the following supplements: L-carnitine, creatine, Q10, vitamin A, niacin, folic acid, vitamin C, vitamin E and probiotic- foods and supplements at least two weeks before study enrolment.
• Unwillingness or inability to have a muscle biopsy performed.

For Sedentary, Pre-frail subjects

• Presence of any contraindication to have MRI scans performed (e.g. pacemaker, intracranial clips etc.).
• Having diabetes mellitus or lower extremity peripheral vascular disease, as these conditions may interfere with interpretation of the dynamic 31P-MRS and NIRS of the lower extremity.
• Participation in a clinical trial within 90 days of screening or more than 4 times in the previous year.
• A history (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol).
• Smoking within 3 months prior to screening and inability to refrain from smoking during the course of the study (from screening to EOS).
• A history or presence of allergy to 5-aminolevulinic acid or porphyrins.
• A history or presence of allergy to lidocaine.
• Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
• Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening.
• Unwillingness or inability to refrain from consuming alcohol within 48 hours before each visit until the end of that visit.
• Unwillingness or inability to refrain from consuming 8 or more units of xanthine containing beverages and foods per day during the entire study.
• Unwillingness or inability to refrain from consuming the following supplements: L-carnitine, creatine, Q10, vitamin A, niacin, folic acid, vitamin C, vitamin E and probiotic- foods and supplements at least two weeks before study enrolment.
• Unwillingness or inability to have a muscle biopsy performed.
• Underlying chronic disease, which, in the opinion of the investigator would interfere with study participation or the validity of the measurements.
• Unintentional weight loss ≤5% of usual body weight during the last 6 months.
• Anorexia or anorexia-related symptoms