Invited Commentary <\/p>\n\n\n\n
April 10, 2025<\/p>\n\n\n\n
Ruane and colleagues1<\/a><\/sup> address a pressing and timely issue: the intersection of olfactory impairment (OI) and aging-related outcomes. While their focus is on OI and its association with mortality, this research emerges in the context of a world with a dramatically aging population. The growth in the prevalence of older adults brings substantial societal, economic, and public health implications, making the detection and prevention of risks in this group essential. Olfaction appears to be a unique canary in the coal mine. While the relationship between OI and mortality has intrigued researchers over the past decade, this current investigation advances our understanding by examining mediating factors such as dementia, frailty, and malnutrition as well as the moderating roles of age, sex, and apolipoprotein E \u03b54 allele status. Notably, this is among the first studies to identify and attribute specific mediators to the heightened mortality risk associated with OI, revealing that these mediators are dynamic and may shift over the time of horizon of which they are studied.<\/a><\/p>\n\n\n\n This longitudinal analysis elucidates the evolving mediating factors that link OI to mortality over time. At 6 years, dementia emerged as the predominant mediator, accounting for 23% of the OI-mortality association, followed by frailty at 11% and malnutrition at 5%. By 12 years, however, the influence of dementia and malnutrition waned, leaving frailty as the sole significant mediator, responsible for 8% of the association. This temporal shift underscores the potential of OI\u2014particularly in the context of neurodegenerative processes or dietary alterations\u2014to serve as a near-term marker of systemic vulnerability and to enhance the precision of identifying imminent age-related risks in older adults. However, the persistent role of frailty reflects a broader narrative of physiological decline, capturing the trajectory from a state of homeostatic symphony to cacophony.2<\/a><\/sup><\/a><\/p>\n\n\n\n The enduring and unique association between OI and frailty has garnered increasing attention. A recent systematic review and meta-analysis underscored OI\u2019s potential as an early biomarker of frailty.3<\/a><\/sup> Although this relationship is particularly compelling, OI demonstrates a stronger predictive value for mortality than other sensory impairments and remains significant even after accounting for declines in physical function.4<\/a><\/sup> This sets olfaction apart from other well-recognized sensory impairments linked to dementia and mortality, such as hearing loss, which has garnered substantial funding and is becoming increasingly mainstream in public health initiatives. Meanwhile, olfaction\u2019s distinctive relationship with longevity underscores OI\u2019s potential untapped utility as a sentinel marker of systemic decline, particularly because it imposes minimal physical limitations compared to other sensory losses.<\/a><\/p>\n\n\n\n At the first follow-up time point in the study by Ruane and colleagues,1<\/a><\/sup> the authors highlight what has long been acknowledged: a primary symptom of neurodegenerative disease and dementia is smell loss, which also has clear potential dietary implications, such as malnutrition. Frailty\u2019s role as a mediator over a longer time course, however, warrants focused attention, especially because it is less well understood, and it remains unclear whether OI acts as a biomarker or plays a causative role in this association. Frailty, characterized by diminished strength, endurance, and physiological reserve, is emblematic of aging-related vulnerability. OI\u2019s association with frailty reinforces its position as an indicator of systemic health, suggesting that olfactory assessments could serve as a noninvasive means to identify individuals at risk of progressive decline. Although more comprehensive olfactory testing that includes measures of peripheral and central olfaction may lend additional insights into the mechanism of the relationship between OI and frailty,5<\/a><\/sup> even the brief psychophysical testing by Ruane et al1<\/a><\/sup> and others3<\/a><\/sup> in population-level studies are sufficient to detect this novel relationship.<\/a><\/p>\n\n\n\n OI\u2019s significance extends beyond frailty, as it intersects with broader systemic and neurological health. While it is well established that OI can serve as an early warning sign for neurodegenerative diseases, its connections to chronic inflammation and cellular aging are equally noteworthy. A conceptual framework for understanding these relationships includes 2 complementary hypotheses. First, OI may reflect systemic processes indicative of underlying disease. Second, it may act as a sentinel marker of cumulative vulnerabilities, creating a feedback loop in which sensory impairments exacerbate physical decline and vice versa. These mechanisms, though distinct, likely interact to shape the trajectory of aging and mortality. Meanwhile, the unique exposure of cranial nerve I to environmental toxins and its direct connection to central nervous system structures further highlights OI\u2019s role as a sensitive indicator of central nervous system health.6<\/a><\/sup> This dual role\u2014serving both as an early marker of neurological disease and as a broader indicator of systemic decline\u2014reinforces the need for routine OI screening as an integral component of holistic geriatric assessments.<\/a><\/p>\n\n\n\n Despite compelling evidence, olfactory testing remains an underutilized tool in geriatric assessments. Given the growing global population of older adults, this is a critical gap in clinical practice. OI testing could offer a noninvasive, cost-effective means to identify individuals at heightened risk of frailty, neurodegeneration, or systemic decline. While current therapeutic interventions for OI are limited, early identification could pave the way for proactive measures, including nutritional support, cognitive monitoring, and interventions targeting frailty. While we may not yet be able to intervene directly on OI, addressing associated comorbidities such as depression or malnutrition is both feasible and impactful. Furthermore, neglecting to measure OI does not diminish its importance; without assessing it, we cannot fully understand its intricate relationship with untoward aging-related outcomes.<\/a><\/p>\n\n\n\n One key challenge lies in the lack of infrastructure and awareness surrounding olfactory testing. Many clinicians may not prioritize OI assessment due to a lack of standardized protocols or training in its interpretation. Furthermore, significant barriers remain, including the absence of reimbursement for olfactory testing. This financial disincentive perpetuates its neglect in clinical settings.7<\/a><\/sup> Addressing these challenges requires a concerted effort to integrate olfactory assessments into routine care and to advocate for policy changes that recognize the value of this diagnostic tool.<\/a><\/p>\n\n\n\n This study by Ruane and colleagues1<\/a><\/sup> explores the novel association between OI and mortality, demonstrating that this association is mediated more immediately by neurodegeneration and, to a lesser extent, by malnutrition and frailty. Over a broader time horizon, frailty emerges as a persistent mediator, underscoring its complex role in aging-related decline. This interplay reinforces the importance of assessing OI as part of a comprehensive approach to understanding aging-related risks.<\/a><\/p>\n\n\n\n