Physical, Cognitive Decline Accelerated in People With Late-Life Depression

Emerging evidence suggests cellular senescence is a hallmark of aging. Cells lose their proliferative capacity, become resistant to apoptosis, and develop a senescence-associated secretory phenotype (SASP) comprising proteins involved in cycle control, intercellular communication, the immune–inflammatory response, and tissue remodeling.

A previously developed SASP index of 22 proteins was found in several studies to be higher in individuals with late-life depression than in non-depressed older adults. Now, Johanna Seitz-Holland, MD, instructor in the Department of Psychiatry at the Brigham, Breno S. Diniz, MD, PhD, of UConn School of Medicine, and colleagues report in Nature Mental Health that the index suggests people with late-life depression are vulnerable to accelerated physical and cognitive decline.

Study Cohort and Variables

The new study was a secondary analysis of Incomplete Response in Late-Life Depression: Getting to Remission (IRL-GREY), a trial of venlafaxine XR conducted between August 2009 and August 2014. The analysis included 426 participants, age 60 or older, who were diagnosed with a non-psychotic major depressive disorder and scored ≥15 on the Montgomery–Åsberg Depression Rating Scale (MADRS).

Participants in IRL-GREY underwent a comprehensive baseline examination:

  • Mental health—An interview to elicit characteristics of depression, MADRS, Anxiety Sensitivity Index, Scale of Suicidal Ideation, and Medical Outcomes Survey–Mental
  • Cognitive functioning—Years of education, Mini-Mental Status Examination, Repeatable Battery for the Assessment of Neuropsychological Status, and portions of the Delis–Kaplan Executive Function System
  • Physical health—Anthropometric data, blood pressure, fasting glucose levels, Cumulative Illness Rating Scale–Geriatrics (CIRS-G), and Medical Outcomes Survey–Physical
  • Self-reported medications

Factor Analyses

In the new study, factor analyses were used to group the baseline clinical variables into four domains:

  • Depression and anxiety severity
  • Cognitive functioning
  • Blood pressure
  • Cardiovascular and cardiometabolic health—body mass index, fasting glucose level, CIRS-G, and Medical Outcomes Survey—Physical


The principal findings were the following:

  • Older and male participants presented with a significantly higher SASP index
  • A higher SASP index was correlated with significantly worse cognitive functioning
  • For both men and women, a higher SASP index was correlated with significantly worse cardiovascular and cardiometabolic health
  • The SASP index was not associated with the severity of depression or anxiety

Interpreting the Findings

That last statement does not contradict the previous studies that demonstrated a higher SASP index in individuals with major depressive disorder. However, the SASP index seems more closely associated with physical health and cognitive functioning than with the severity of depression and anxiety symptoms in individuals with late-life depression.

Depression shortens life expectancy if it undermines an individual’s adherence to pharmacotherapy for medical diseases and interferes with healthy lifestyle choices. This analysis suggests treatment of depression should include lifestyle modifications that target general health, such as weight loss and exercise programs, and optimized control of chronic medical conditions such as diabetes, hypertension, and hyperlipidemia.

Reasoning in the opposite direction, treatments that clear senescent cells or modify SASP-mediated pathways could be innovative approaches to improving outcomes for adults with late-life depression.

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