Metabolic Control of Aging and Disease - the MetAGE Deep Phenotyping Cohort

The ongoing increase in human life expectancy is steadily reshaping the demographic landscape, leading to a higher proportion of older adults, many of whom suffer from multiple health conditions. These unprecedented demographic shifts come at a significant socioeconomic cost, as aging stands as the primary risk factor for chronic disabilities and disorders such as cardiovascular diseases, dementia, type 2 diabetes, obesity, steatotic liver disease and infections. Consequently, promoting healthy aging emerges as one of the most pressing societal challenges in the foreseeable future, underscoring the urgent need for clinically validated strategies to extend the disease-free phase of life, known as health span.

The Pro-MetAGE prospective cohort as part of the clinical program of the MetAGE Cluster of Excellence (Austrian Science Fund # 10.55776/COE14) will focus on understanding the metabolic dysregulation associated with aging in a metabolic at-risk population. Metabolic control, which encompasses various aspects and is influenced by numerous aging indicators, might be the primary driver of age-related diseases. For instance, contemporary markers of biological age, such as epigenetic clocks based on DNA methylation and cellular senescence markers, correlate more closely with metabolic processes like nutrient sensing and mitochondrial function rather than genome stability or telomere length.

Aging entails a gradual deterioration of several fundamental metabolic processes, including lipostasis (fat metabolism), proteostasis (protein homeostasis), polyamine metabolism, and mitochondrial function. These intracellular changes are compounded by alterations in intercellular and interorgan communication, affecting brain-organ interactions and immune function. The decline in these crucial processes can disrupt the regulatory mechanisms of metabolic control in a manner influenced by sex and gender. Consequently, the loss of metabolic control may exacerbate other aging processes, setting off a detrimental cycle of accelerated aging.

Disruption in metabolic regulation caused by calorie-rich diets, disturbed circadian rhythms, or sedentary lifestyle can lead to a diverse set of health issues known collectively as metabolic syndrome. These medical conditions, including obesity, high blood pressure, elevated lipid levels, insulin resistance, and high blood sugar, contribute to the development of prevalent age-related diseases such as cardiovascular disease, type 2 diabetes, retinal degeneration and metabolic dysfunction-associated steatotic liver disease, formerly known as nonalcoholic fatty liver disease, affecting millions of older individuals globally. Additionally, there exists a significant link between metabolic imbalance and dysfunction in the immune system, resulting in heightened susceptibility to infections, diminished response to vaccinations, and various neuropsychiatric disorders, especially depression. Hence, understanding the mechanisms underlying metabolic dysregulation holds immense importance in devising preventive measures against some of the most debilitating age-related ailments.

The proposed research project aims to prospectively identify and validate aging biomarkers in relation to age- and sex-related cardiometabolic changes in young and old individuals, who are lean or obese/overweight (i.e. a metabolic at-risk population) with regard to lipostasis, proteostasis, polyamine metabolism, mitochondrial function, inflammation and cellular senescence. The goal is to gain insights into the interaction of obesity related metabolic alteration and aging, and the relevance of loss of metabolic control in the development of age-related diseases in order to build a foundation for targeted drug- and lifestyle interventions in future studies.

Inclusion criteria

Group 1 - Lean, young adults (n = 150)

• Age 18 - 35 years
• Body mass index (BMI) ≥ 18.5 and ≤ 24.9 kg/m2 (≥ 12 months)

Group 2 - Overweight, young adults (n = 150)

• Age 18 - 35 years
• BMI ≥ 28kg/m2 (≥ 12 months)

Group 3 - Lean, older adults (n = 150)

• Age ≥ 60 years
• BMI ≥ 18.5 and ≤ 24.9 kg/m2 (≥ 3 years)

Group 4 - Overweight, older adults (n = 150)

• Age ≥ 60 years
• BMI ≥ 28 kg/m2 (≥ 3 years)
• Subgroup A (n=75): with pre-existent cardiovascular disease defined as: history of myocardial infarction or evidence of coronary artery disease irrespective of revascularization status or history of ischemic or hemorrhagic stroke or presence of peripheral artery disease or heart failure with preserved ejection fraction (NYHA Class I-II).
• Subgroup B (n=75): without pre-existent cardiovascular disease

Group 5 - Nonagenerians Age ≥ 90 (n = 50)

• Age ≥ 90 years
• BMI ≥ 18.5 kg/m2 (≥ 3 years)

Exclusion criteria

Group 1 - Lean, young adults (n = 150)

• Highly physical active (i.e. > 5 times sporting activity / week with moderate to high intensity [heart rate 140 - 200bpm])
• Special diets (i.e. ketogenic diet and time-restricted eating)
• Clinically significant metabolic or endocrine disorders
• Claustrophobia
• drug abuse, alcohol > 15 drinks/week
• Heart failure, cardiovascular disease, immunosuppressive therapies, chronic inflammatory diseases and active oncologic conditions
• Metal implants that prohibit 3T MRI
• Pregnancy or breastfeeding

Group 2 - Overweight, young adults (n = 150)

• Highly physical active (i.e. > 5 times sporting activity / week with moderate to high intensity [heart rate 140 - 200bpm])
• Special diets (i.e. ketogenic diet and time-restricted eating)
• Active anti-obesity treatment (e.g. glucagon-like peptide 1 (GLP-1) analogues, polyagonists, naltrexone and bupropion)
• Clinically significant metabolic or endocrine disorders
• Claustrophobia
• drug abuse, alcohol > 15 drinks/week
• Heart failure, cardiovascular disease, immunosuppressive therapies, chronic inflammatory diseases and active oncologic conditions
• Metal implants that prohibit 3T MRI
• Pregnancy or breastfeeding

Group 3 - Lean, older adults (n = 150)

• Highly physical active (i.e. > 5 times sporting activity / week with moderate to high intensity [heart rate 140 - 200bpm])
• Special diets (i.e. ketogenic diet and time-restricted eating)
• Diabetes, overt hypo/hyperthyroidism
• Claustrophobia
• drug abuse, alcohol > 15 drinks/week
• Metal implants that prohibit 3T MRI
• Known severe cardiovascular diseases (i.e. PAD IIa or higher, advanced heart failure = left ventricular ejection fraction (LVEF) < 35% or NYHA Class III-IV)
• No previous heart failure, cardiovascular disease, immunosuppressive therapies, chronic inflammatory diseases and active oncologic conditions up until the age of 35 years.
• Life-threatening conditions with a life expectancy of less than 1 year or any other condition that would jeopardize proband safety/adherence while participating in this trial.

Group 4 - Overweight, older adults (n = 150)

• Special diets (i.e. ketogenic diet and time-restricted eating)
• Diabetes, overt hypo/hyperthyroidism
• Active anti-obesity treatment (e.g. GLP-1 analogues, polyagonists, naltrexone and bupropion)
• Claustrophobia
• drug abuse, alcohol > 15 drinks/week
• Metal implants that prohibit 3T MRI
• No previous heart failure, cardiovascular disease, immunosuppressive therapies, chronic inflammatory diseases and active oncologic conditions up until the age of 35 years.
• Life-threatening conditions with a life expectancy of less than 1 year or any other condition that would jeopardize proband safety/adherence while participating in this trial.

Group 5 - "healthy" Nonagenerians Age ≥ 90 (n = 50)

• Claustrophobia
• Clinically significant cognitive impairment compromising study adherence
• Metal implants that prohibit 3T MRI
• Life-threatening conditions with a life expectancy of less than 1 year or any other condition that would jeopardize proband safety/adherence while participating in this trial.