Tirzepatide to Slow Biological Aging

Primary Objective To estimate the potential effect of tirzepatide on biological aging using epigenetic age (based on established DNA methylation-based clocks), among people 55-70 years of age with an indication for tirzepatide weight loss therapy.

The principal investigator (PI) will measure DNA methylation-based aging clocks (DNAmAge, DNAm PhenoAge, DNAm GrimAge and DunedinPACE) before and after a 24-W course of tirzepatide. The primary analysis will determine whether tirzepatide treatment leads to a statistically significant change in biological age as indicated by these clocks. The PI will specifically assess epigenetic age acceleration (epigenetic age minus chronological age) and the pace of aging metric.

Secondary and Exploratory Objectives

Among people 55-70 years of age with an indication for tirzepatide weight loss therapy, the is aim to:

• Estimate self-reported tolerability and acceptability of tirzepatide during the study period
• Estimate changes in BMI and weight over 24 W of tirzepatide therapy, and in off-drug follow-up, between W 24 and 36
• Estimate changes in physical function over 24 W of tirzepatide and, in off-drug follow-up, between W 24 and 36
• Estimate changes in inflammatory, aging and neurocognitive biomarker profiles over 24 W of tirzepatide therapy, and in off-drug follow-up, between W 24 and 36
• Estimate changes in other biological hallmarks/markers of aging
• Explore relationships between the above outcomes

Inclusion criteria

• Age 55-70 years
• BMI ≥ 30 kg/m² or ≥ 27 kg/m² if also with ≥ 1 weight-related comorbidity
• If taking anti-inflammatory or blood-pressure-/lipid-/glucose-lowering medications, no change in dose for ≥12 weeks prior to entry and no plans to dose escalate for the study duration
• Willing and able to provide written informed consent and undergo all required study procedures

Exclusion criteria

• BMI >35 kg/m²
• Uncontrolled or end-stage, comorbid, cardiometabolic disease, in the opinion of the site investigator
• Significant neurocognitive impairment, in the opinion of the site investigator
• Current or planned use of medications for the treatment of obesity, or medications likely to cause significant changes in weight, during the study period (see prohibited medications, section 6.0)
• Use of insulin
• Plans to newly engage in formal, intensive physical activity or diet (such as ketogenic or very low carbohydrate) programs during the study period
• Active eating disorder
• Use of human growth hormone, tesamorelin, supraphysiologic testosterone or estradiol (stable doses for contraception, hypogonadism or other indications for exogenous sex steroid replacement therapy permitted) or anabolic steroids <12 W prior to entry, unless on a stable dose for >24 W prior to entry, or plans to start any of these medications while on study
• Active, severe delayed gastric emptying
• Prior bariatric surgery or major gastric surgery or plans for weight reduction surgery while on study
• Known diabetic retinopathy
• Personal or first-degree relative history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
• Untreated, poorly controlled or previously undiagnosed thyroid disease
• History of chronic pancreatitis
• History of suicidal attempts or active suicidal ideation, in the opinion of the site investigator
• Known allergy/sensitivity to GLP-1RA or GIPRA
• Use or planned use of any immunomodulatory therapy or investigational therapy during the study period or use of an investigational therapy within 30 days of entry
• Any other medical condition that, in the opinion of the investigator, would place the subject at increased risk for participation.
• Pregnancy, nursing or plans for either during the study period