Conceptualizing late-life depression (LLD) in context of aging provides insights into how the underlying neurobiology of LLD contributes to adverse clinical outcomes. It may be particularly useful to consider LLD in relationship to accelerated aging or biological aging processes that occur more rapidly or more severely than expected (Christman et al., Reference Christman2020). This relationship between depression and aging is likely bidirectional: depression may accelerate aging processes, while accelerated aging processes, particularly those involving the brain, may increase the risk for developing new-onset or recurrent depressive episodes (Andreescu et al., Reference Andreescu2019; Rutherford et al., Reference Rutherford, Taylor, Brown, Sneed and Roose2017). Among the many implications of an “accelerated aging hypothesis of late-life depression” is the utility of considering LLD as a geriatric syndrome that coexists with and is influenced by other deleterious geriatric syndromes, including frailty.

Frailty is a syndrome characterized by accelerated aging in multiple organ systems, defined by weakness, medical morbidity, decreased physical function, fatiguability, and unintentional weight loss (Fried et al., Reference Fried2001). Frailty and depression are highly comorbid, with approximately 40% of frail elders having depression and approximately 40% of individuals with LLD exhibiting frailty (Soysal et al., Reference Soysal2017). Such cross-sectional associations are supported by longitudinal studies further demonstrating this reciprocal risk. Depression is associated with worsening trajectories in functional status, including reduced walking speed and hand strength (Lever-van Milligen et al., Reference Lever-van Milligen, Lamers, Smit and Penninx2017), and older depressed adults are more likely to develop frailty than nondepressed individuals (2.6 increased hazard) (Chang et al., Reference Chang2022). Conversely, both pre-frail and frail individuals are at increased risk for depression (1.86 and 2.46 odds, respectively) (Marconcin et al., Reference Marconcin2022) and within-person increases in frailty are strongly associated with concomitant worsening depression (Mayerl et al., Reference Mayerl, Stolz and Freidl2020). However, despite clear epidemiological data supporting reciprocal relationships, the underlying neurobiological mechanisms underlying these relationships are unclear. It is similarly unclear what interactive effects frailty and depression have on the brain.

The pilot study reported by Shuster and colleagues in International Psychogeriatrics (Shuster et al., Reference Shuster2023) begins to address these questions. This study examines structural and microstructural brain differences between older, never-depressed healthy individuals and individuals with comorbid LLD and frailty (defined as either pre-frail or frail). Intriguingly, the authors found group differences only in the white matter microstructure obtained from diffusion tensor imaging (DTI), specifically white matter mean diffusivity (MD). The depressed and frail group exhibited increased MD extending over several white matter tracts involved in inter-hemispheric communication, emotional, and cognitive processing. They did not observe group differences in regional subcortical volumes, cortical thickness, or other DTI measures such as fractional anisotropy (FA).

The ultimate significance of this report depends on how we interpret this specific finding and how it guides this area of research. The authors interpret the difference in MD as potentially representing longer-term effects of cytotoxic edema, occurring within the white matter’s glial cells and potentially secondary to neuroinflammation. This is a reasonable hypothesis, as MD is sensitive to cellular swelling that restricts diffusion (Schlaug et al., Reference Schlaug, Siewert, Benfield, Edelman and Warach1997) and increases can occur chronically in context of inflammation or following hypoxia. It is worth noting that, despite the clinical neuroscience research community having substantial experience using MRI-based diffusion imaging, interpretation of DTI results can be challenging. As most cerebral white matter voxels contain multiple fiber groups with varying trajectories, there are substantial limits for the ability for many DTI measures, such as FA, to support definitive conclusions about the underlying white matter microstructure (Figley et al., Reference Figley, Uddin, Wong, Kornelsen, Puig and Figley2021). However, as MD allows for equal weight across all three axes of the diffusion tensor, MD may be more robust to crossing fibers and be a more reliable marker of how tissues are constraining water diffusion within each voxel (Figley et al., Reference Figley, Uddin, Wong, Kornelsen, Puig and Figley2021). The increased MD values observed in the identified regions by Shuster and colleagues suggest that, when compared with never-depressed participants, individuals with LLD and frailty exhibit loss of white matter structure in those regions.

Several possible mechanisms could both explain the observed neuroimaging findings and contribute to the bidirectional relationship between depression and frailty. This inflammation hypothesis proposed by Shuster and colleagues is reasonable as pro-inflammatory markers are associated with both LLD and frailty, as well as DTI measures of subcortical white matter integrity (Aronica et al., Reference Aronica, Enrico, Squarcina, Brambilla and Delvecchio2022). However, there are alternative hypotheses. For example, higher vascular burden is associated with LLD, frailty, and white matter pathology (Stewart, Reference Stewart2019; Taylor et al., Reference Taylor, Aizenstein and Alexopoulos2013). Similarly, LLD can promote sedentary behavior and isolation, or be a result of chronic pain or physical disabilities. Thus, depression may contribute to muscle atrophy, deconditioning, and frailty (Brown et al., Reference Brown2022; Taylor et al., Reference Taylor2022). Notably, the contributing factors considered in these alternative hypotheses are themselves associated with increased inflammation, further supporting potential common shared pathways for the bidirectional relationship between depression and frailty.

Geriatric syndromes and accelerated aging processes such as LLD and frailty do not occur in isolation. It is important to consider not only the interrelationship between depression and frailty but also how these syndromes are related to or may influence other negative aging outcomes. Previous work published in International Psychogeriatrics demonstrates that depression not only increases the risk of developing frailty (Chang et al., Reference Chang2022), but comorbid depression and frailty also independently and interactively increase mortality risk, particularly in the pre-frail population (Ruiz-Grao et al., Reference Ruiz-Grao, Sanchez-Jurado, Molina-Alarcon, Hernandez-Martinez, Avendano Cespedes and Abizanda2021). Other studies published in International Psychogeriatrics additionally demonstrate that frailty increases the risk for developing cognitive decline and dementia (Wallace et al., Reference Wallace, Hunter, Theou, Fleming, Rockwood and Brayne2021), a relationship that may be mediated by poor sleep quality (Kaur et al., Reference Kaur2019).

Cumulatively, the broader literature supports a bidirectional scientific model wherein medical illnesses common in aging, such as hypertension, diabetes, and musculoskeletal pain syndromes, have deleterious effects that are at least partially mediated by pro-inflammatory processes. These processes contribute to physical frailty and disability, also increasing the allostatic load in the brain resulting in regional atrophy, loss of white matter microstructure, and increased neuropathology that may be characterized as accelerated aging (Andreescu et al., Reference Andreescu2019; Christman et al., Reference Christman2020). These changes then increase vulnerability for developing depression and cognitive impairment. Such neuropathology may in turn hasten physical decline and worsen frailty. This may be mediated by discrete cognitive deficits common in LLD, such as difficulty with initiation of activities, loss of interest, apathy and motivational disturbances, and decreased willingness to expend effort (Taylor et al., Reference Taylor2022). In context of medical infirmity, this could hasten sarcopenia, deconditioning, and frailty. It may also contribute to increased mortality.

While this International Psychogeriatrics report (Shuster et al., Reference Shuster2023) advances our understanding of this model, its cross-sectional nature limits our ability to make causal inferences. Aging is a dynamic process and examining within-subject trajectories of change is an informative, powerful approach. Other limitations that should be considered when interpreting these data include the smaller sample size that, as noted by the authors, reduces statistical power and increases risk for type II errors. Additionally, frailty was defined using a clinical assessment questionnaire, and future work may benefit from objective, direct measures of function, such as grip strength or gait speed. Finally, while the report characterizes neuroimaging findings in a depressed-frail phenotype, the study did not include non-frail depressed individuals or frail but never-depressed individuals. Thus, independent or overlapping contributions of depression and frailty on the neuroimaging findings cannot be disentangled.

Limitations aside, this pilot study from Shuster and colleagues provides a solid direction for future work in this clinically relevant area. It will be critical to disentangle both common and unique mechanistic pathways underlying the reciprocal relationship between depression and frailty. This should be examined broadly, including not only neuroimaging measures but also biological measures of immune system function and inflammation, measures of medical morbidity and vascular function, and potentially other established markers of accelerated aging, including telomere length. It also should include environmental assessments and measures of physical function, as well as measures of lifestyle factors including physical activity. As noted in their report, future work would benefit from larger samples and longitudinal designs, as well as a wider range of participants, including non-frail individuals with LLD, or frail but never-depressed participants. Ultimately, this work should provide mechanistic targets suitable for intervention, which could include anti-inflammatory approaches or movement-based interventions designed to slow or reduce frailty and improve physical condition.