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Does Late-Life Depression Accelerate Aging?

  • Helen Lavretsky
    Correspondence
    Send correspondence and reprint requests to Helen Lavretsky M.D., M.S., Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, Los Angeles, CA 90024.
    Affiliations
    Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA
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Published:January 10, 2023DOI:https://doi.org/10.1016/j.jagp.2023.01.002
      Depression in older adults occurs in the context of biological aging that contributes to the clinical symptoms, biomarkers, and the course of the disease.
      • Bersani FS
      • Mellon SH
      • Reus VI
      • et al.
      Accelerated aging in serious mental disorders.
      Neurobiology of aging and late-life mental disorders share features of increased cellular senescence, inflammation, and reduced mitochondrial function. In addition, serious mental disorders (SMDs), including major depression, are associated with an increased risk of medical illnesses and premature mortality from natural causes, with lifespans up to 25 years shorter than the general population, even after controlling for suicide.
      • Bersani FS
      • Mellon SH
      • Reus VI
      • et al.
      Accelerated aging in serious mental disorders.
      Patients with late-life depression (LLD) are also at increased risk for developing somatic diseases that are typically associated with advanced age, such as cardiovascular diseases, metabolic syndrome, immune dysregulation, and dementia.
      • Bersani FS
      • Mellon SH
      • Reus VI
      • et al.
      Accelerated aging in serious mental disorders.
      The causes of this are likely multifactorial, including genetic predisposition, biological changes associated with early-life adversity, and multiple lifestyle factors. Lifestyle factors, while important, do not fully explain the increased mortality and morbidity in these individuals, and consequently, “accelerated biological aging” is increasingly being seen as an intrinsic factor in mental disorders.
      • Lindqvist D
      • Epel ES
      • Mellon SH
      • et al.
      Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.
      • Darrow SM
      • Verhoeven JE
      • Revesz D
      • et al.
      The Association between psychiatric disorders and telomere length: a meta-analysis involving 14,827 persons.
      This observation takes LLD and SMDs out of the realm of “mental disorders” or brain diseases, but rather points to the whole-body multisystem disorders that are present with psychological symptoms.
      • Darrow SM
      • Verhoeven JE
      • Revesz D
      • et al.
      The Association between psychiatric disorders and telomere length: a meta-analysis involving 14,827 persons.
      Understanding these underlying mechanisms should offer novel preventative and therapeutic opportunities to improve physical and mental health and increase the lifespan of older adults. However, it remains unclear whether these markers are causally related to depression, or simply coexist with mental disorders. Below, we discuss several potential biomarkers that have been linked to greater morbidity- and mortality in LLD and other mental disorders, including the novel marker proposed by Mastrobattista, Diniz and colleagues.
      • Mastrobattista
      • Lenze
      • Reynolds
      • et al.
      Late-life depression is associated with increased levels of GDF-15, a pro-aging mitokine.

      TELOMERE LENGTH

      Telomere length (TL) determinations, generally in peripheral leukocytes (LTL), are the most widely studied markers of biological aging in SMDs.
      • Lindqvist D
      • Epel ES
      • Mellon SH
      • et al.
      Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.
      Telomeres, which cap DNA strands, protect chromosomes from damage and replicative senescence.
      • Lindqvist D
      • Epel ES
      • Mellon SH
      • et al.
      Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.
      Most studies have replicated findings of LTL shortening in chronic psychological stress and major depressive disorder (MDD)
      • Darrow SM
      • Verhoeven JE
      • Revesz D
      • et al.
      The Association between psychiatric disorders and telomere length: a meta-analysis involving 14,827 persons.
      Increases in inflammation and oxidative stress and stress hormones are prime candidates for the causal processes.
      • Lindqvist D
      • Epel ES
      • Mellon SH
      • et al.
      Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.
      Because these biochemical factors can, themselves, be associated with physical disease and decreased life span, it is uncertain whether LTL shortening directly relates to health and age-associated outcomes, or rather, points to a toxic cellular milieu, or both
      • Lindqvist D
      • Epel ES
      • Mellon SH
      • et al.
      Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.
      ,
      • Blackburn EH
      • Epel ES
      • Lin J
      Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection.

      DNA METHYLATION AND EPIGENETIC CLOCKS

      More recently described markers, based on methylation of the genome, may provide even stronger estimates of biological age.
      • Declerck K
      • Vanden Berghe W
      Back to the future: Epigenetic clock plasticity towards healthy aging.
      Age-associated site-specific methylation changes occur with surprising regularity across individuals and in some cases across tissues. Assessing such changes at specific 5’-C-phosphate-G-3’ (CpG) sites can indicate “DNA methylation age” or “epigenetic age” (EpiAge). Correlations between EpiAge and chronological age are remarkably high, with correlations of up to 0.96.
      • Horvath S
      DNA methylation age of human tissues and cell types.
      Advanced epigenetic age is associated with many serious medical illnesses and predicts mortality better than chronological age alone.
      • Han LKM
      • Aghajani M
      • Clark SL
      • et al.
      Epigenetic aging in major depressive disorder.
      Several different measures of epigenetic aging (termed “clocks”) are strongly associated with chronological age and certain illnesses and mortality, each has specific properties and meanings. For example, the Horvath clock was the first developed
      • Horvath S
      DNA methylation age of human tissues and cell types.
      and is based on methylation patterns of a set of 353 CpG's (out of 21,369 examined) that was “trained” on predicting chronological age and then validated in independent samples; it was found to not only accurately predict chronological age, but to be more strongly associated with biological aging parameters. Han et al used a newer DNA methylation algorithm that examined virtually the entire 28 million CpG sites to assess epigenetic aging in MDD
      • Han LKM
      • Aghajani M
      • Clark SL
      • et al.
      Epigenetic aging in major depressive disorder.
      and found a set of 80,000 CpG sites that revealed a modest but significant acceleration of EpiAge in MDD. Pathway analysis of the top CpG sites associated with epigenetic aging in MDD implicated neurogenesis, neuron differentiation, and regulation of neuron death.
      • Han LKM
      • Aghajani M
      • Clark SL
      • et al.
      Epigenetic aging in major depressive disorder.
      While telomere length and epigenetic clocks significantly correlate with chronological age and predict disease and mortality, they are independent from each other.
      • Puterman E
      • Epel ES
      • Lin J
      • et al.
      Multisystem resiliency moderates the major depression-telomere length association: findings from the Heart and Soul Study.
      However, both TL and methylation are affected by the environment and lifestyle behaviors (e.g., sleep, diet, smoking, and exercise), which has logistic implications for clinical use and the interpretation of the results.
      • Puterman E
      • Epel ES
      • Lin J
      • et al.
      Multisystem resiliency moderates the major depression-telomere length association: findings from the Heart and Soul Study.

      IMMUNOSENESCENCE AND INFLAMMAGING

      Aging-associated systemic, low-grade inflammation, termed “inflammaging,” is characterized by chronically increased levels of inflammatory cytokines and acute phase reactants and may underlie the progression of pathological senescence processes, including those in the brain.
      • Picard M
      • McEwen BS
      Psychological stress and mitochondria: a systematic review.
      While chronic low-level inflammation has repeatedly been demonstrated in MDD and other SMDs,
      • Bersani FS
      • Mellon SH
      • Reus VI
      • et al.
      Accelerated aging in serious mental disorders.
      ,
      • Lindqvist D
      • Epel ES
      • Mellon SH
      • et al.
      Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.
      its role in accelerating biological aging and its utility as a biomarker of biological aging have yet to be adequately studied.

      MITOCHONDRIAL DYSFUNCTION

      Mitochondrial dysfunction may reflect, and perhaps also play a role in, accelerated biological aging, and is being studied in mental disorders.
      • Mastrobattista
      • Lenze
      • Reynolds
      • et al.
      Late-life depression is associated with increased levels of GDF-15, a pro-aging mitokine.
      The relationships between mitochondrial dysfunction and its associated consequences of impaired oxidative metabolism, especially in SMD's, are complex and remain incompletely understood. As Mastrobattista, Diniz et al. stated in their article “when damaged, mitochondria elicit a stress response by releasing various proteins and peptides known as mitokines.”
      • Mastrobattista
      • Lenze
      • Reynolds
      • et al.
      Late-life depression is associated with increased levels of GDF-15, a pro-aging mitokine.
      ,
      • Assadi A.
      • Zahabi A.
      • Hart R.A.
      GDF15, an update of the physiological and pathological roles it plays: a review.
      Mitochondrial dysfunction and the release of mitokines have also been associated with abnormal regulation of apoptosis and increased oxidative stress markers that contribute to accelerated aging associated with MDD.
      • Mastrobattista
      • Lenze
      • Reynolds
      • et al.
      Late-life depression is associated with increased levels of GDF-15, a pro-aging mitokine.
      ,
      • Assadi A.
      • Zahabi A.
      • Hart R.A.
      GDF15, an update of the physiological and pathological roles it plays: a review.
      As the article in this issue summarizes, “there is accumulating evidence that growth differentiation factor 15 (GDF-15) plays a significant role in biological aging and the development of age-related diseases. GDF-15 is involved in biological pathways relevant to aging, such as energy homeostasis, stress response, and inflammatory regulation.”
      • Mastrobattista
      • Lenze
      • Reynolds
      • et al.
      Late-life depression is associated with increased levels of GDF-15, a pro-aging mitokine.
      ,
      • Assadi A.
      • Zahabi A.
      • Hart R.A.
      GDF15, an update of the physiological and pathological roles it plays: a review.
      ,
      • Bansal Y.
      • Kuhad A.
      Mitochondrial dysfunction in depression.
      GDF-15 is shown to be a pleiotropic molecule, and its biological effects are probably dependent on different biological contexts as well as chronological age.”
      • Mastrobattista
      • Lenze
      • Reynolds
      • et al.
      Late-life depression is associated with increased levels of GDF-15, a pro-aging mitokine.
      ,
      • Assadi A.
      • Zahabi A.
      • Hart R.A.
      GDF15, an update of the physiological and pathological roles it plays: a review.
      ,
      • Bansal Y.
      • Kuhad A.
      Mitochondrial dysfunction in depression.
      In this issue of the Journal, Mastrobattista, Diniz, and colleagues provide another example of a potential biomarker of accelerated aging by studying circulating levels of the GDF-15 in 393 older adults with MDD in association with depression severity, physical comorbidity burden, age of onset of first depressive episode, and cognitive performance. The primary hypothesis for the study was that higher GDF-15 levels would be observed in depressed participants compared to nondepressed controls, and associated with higher severity of depressive symptoms, a higher burden of physical comorbidity, older age of onset of first depressive episode, and poorer cognitive performance. The authors found that depressed older adults had significantly higher GDF-15 serum than the nondepressed controls. Among depressed individuals, those with high GDF-15 had higher levels of comorbid physical illness, lower executive cognitive functioning, and a higher likelihood of having late-onset depression. Thus, these results support the role of GDF-15 as a marker of age-related biological changes that can serve as a biological pathway between depression and accelerated biological and cognitive aging.
      The current evidence points to the greatest value of biomarkers of aging in their clinical utility. Among the most important questions is whether biological aging in mental disorders can be decelerated with appropriate interventions.
      • Lindqvist D
      • Epel ES
      • Mellon SH
      • et al.
      Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.
      ,
      • Lin J
      • Epel E
      • Blackburn E
      Telomeres and lifestyle factors: roles in cellular aging.
      Behavioral and lifestyle interventions can likely attenuate the pace of certain types of biological aging.
      • Lin J
      • Epel E
      • Blackburn E
      Telomeres and lifestyle factors: roles in cellular aging.
      Preliminary evidence also suggests that certain pharmacological therapies may delay biological aging.
      • Lin J
      • Epel E
      • Blackburn E
      Telomeres and lifestyle factors: roles in cellular aging.
      ,
      • Bersani FS
      • Lindqvist D
      • Mellon SH
      • et al.
      Telomerase activation as a possible mechanism of action for psychopharmacological interventions.
      At this time, the use of aging biomarkers for clinical purposes may not be helpful, due to the differences in assay techniques, lack of normative ranges, and lack of knowledge about the effect of covariates. However, biomarker testing may be useful in longitudinal tracking within individuals to assess the trajectories of these markers and possibly to indicate whether therapeutic interventions are effective in reversing biological aging.
      With progress in our understanding of the role of biomarkers of biological aging, with a new focus on subcellular components and processes in addition to neurotransmitters, we may move from the current belief that mental disorders are brain disorders to a broader concept of the multisystem biological imbalance including biochemical system disturbances (e.g., glucocorticoids, inflammation, oxidative stress) that can broaden our view of therapeutic modalities for achieving emotional well-being. Future research may lead us beyond the pure consensus and phenomenology-based diagnostic system that is the currently used DSM-5TR diagnostic and statistical manual
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders (Fifth ed.).
      that guides our clinical and research practices and overlooks broad biological underpinnings of psychiatric pathology and limits our therapeutic approaches. With this conceptual switch, a new understanding of a “Whole person” approach to the healing of psychiatric disorders can make more sense, and hopefully, be more successful than all presently narrowly brain-focused somatic (e.g., psychotropic drugs, various brain stimulation techniques), and psychotherapeutic modalities. This scientific direction can revolutionize the care for older adults with mental disorders, and address the multifaceted neurobiology of aging.
      This work was partially supported by the K24 AT009198 to Dr. Lavretsky. Helen Lavretsky does not have any conflicts of interest to declare. Helen Lavretsky is the sole contributor of this editorial.

      DATA STATEMENT

      The data has not been previously presented orally or by poster at scientific meetings.

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      Linked Article

      • Does Late-Life Depression Accelerate Aging?
        The American Journal of Geriatric PsychiatryVol. 31Issue 1
        • Preview
          Depression in older adults occurs in the context of biological aging that contributes to the clinical symptoms, biomarkers, and the course of the disease.1 Neurobiology of aging and late-life mental disorders share features of increased cellular senescence, inflammation, and reduced mitochondrial function. In addition, serious mental disorders (SMDs), including major depression, are associated with an increased risk of medical illnesses and premature mortality from natural causes, with lifespans up to 25 years shorter than the general population, even after controlling for suicide.
        • Full-Text
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      • Corrigendum to “Does Late-life Depression Accelerate Aging?” [Am J Geriatr Psychiatry 31 (2023) 10–13]
        The American Journal of Geriatric Psychiatry
        • Preview
          The editor regrets that the printed version of the above editorial commentary in the January, 2023 edition of AJGP, contained several errors. The correct and final version of the editorial commentary appears in this issue. It offers a clear and robust discussion of the interface between geroscience and geriatric mental health and of the importance and innovation of the finding presented in the original research article.
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