Aging, Senescence, and the Human Condition

What I have enjoyed most about writing for Sensible Medicine has been the give and take with our readers. Whether it is in the comment section, emails, or essay responses, I have been thrilled by the thoughtful and often challenging responses. I am lucky enough to be at a point in my career when I could switch from journals to substack where this give and take is possible.

When we started Sensible Medicine we wrote “Our goal is a showcase a range of ideas and opinions, and we may disagree with each other. Once upon a time, that was how progress occurred. We hope to return to a vigorous dialogue.” What follows began as an email from a reader who didn’t agree with what he heard from me on an episode of the podcast and in one of my posts. He makes some great points.

Adam Cifu

Recent content on Sensible Medicine discussed a NEJM study examining the cardiovascular safety of testosterone replacement therapy in hypogonadal men. Reading and listening to this commentary, I felt that several points, particularly those concerning the concepts of 'aging' and the 'human condition', warranted deeper consideration.

Adam Cifu discussed the physician's role in managing symptoms that could be considered part of the ‘human condition’. Although not formally defined, I interpret the 'human condition’ as an implication that aging is an expected part of life's vicissitudes. Dr. Cifu expressed his distaste for what he referred to as “cosmetic medicine”. After all, isn't the decline in physiological and metabolic functionality a fait accompli? In “As You Like It”, William Shakespeare writes, “and so from hour to hour we ripe and ripe, and then from hour to hour we rot and rot; and thereby hangs a tale.”

I suggest that it is crucial for us, as physicians and physician-scientists, to distinguish between aging and senescence. Aging encompasses a spectrum of chronological changes in biological and physiological function that occur over time, while senescence embodies the gradual deterioration in physiological function that accompanies this aging process. Senescent changes display a great deal of individual heterogeneity, with each individual manifesting idiosyncratic phenotypic senescent changes as they age. These changes can be evident upon physical examination, or they may remain entirely clinically silent, eluding even the most perceptive physician.

Chronological age is often used, at least in part, as an indirect biomarker for aging. However, given the phenotypic heterogeneity of senescence, it is insufficient to use age alone as a biomarker for the senescent changes associated with aging. An 89-year-old woman in Monaco, leisurely strolling through the Jardin Exotique, strikes me as aging at a vastly different rate compared to an individual of the same age who has been grappling with a multitude of chronic health conditions for decades.

As a neurologist, and more specifically, a behavioral neurologist, I find the cultural and medical landscape brimming with misinformation regarding the concept of 'normal aging'. Should these 'senior moments' truly be considered benign?

As it turns out, most cognitive processes remain relatively stable as we age, while others may even improve over time. 'Senior moments', as I understand them, refer to more frequent difficulties in word finding – that all too familiar 'tip-of-the-tongue' phenomenon. We do have some evidence suggesting that phonemic fluency, or the measure of how quickly and easily someone can generate words that begin with a specific letter or sound, appears to decline with advancing age. However, the reason for this might be tied to these aforementioned senescent changes. The so-called benign 'white matter hyperintensities' frequently observed in our MRI brain scans often accumulate with age and are strongly linked with these fluency changes. White matter changes, it should be said, are reflective of underlying vascular pathology and not ipso facto related with chronological age.

Other trends, such as a mild decrease in cerebral volume, are also observed with what is typically called normal aging. However, the data used to draw these conclusions are derived from autopsy studies in addition to longitudinal and cross-sectional studies that suffer from a multitude of methodological limitations - many of these sorts of limitations are discussed in detail on Sensible Medicine. There is hope for autopsy studies, however, with Emma Nichols and colleagues (Nichols et al, 2023) performing a crucial harmonization of neuropathology in their investigation of brain-tissue analysis across a diverse population. A refreshing bit of clarity for an area of study that for far too long has been hamstrung by flawed but otherwise well-intentioned study designs.

So, I ask you and your readers: is age the etiology of these changes, or are we observing neurocognitive sequelae associated with an accumulation of cerebral pathology? Further, how much of this pathology should we attribute to senescence and how much to pathology associated with identifiable medical disease? One could argue that there is no 'exclusive or' situation here, but we must concede that it is, at the very least, unclear what is specifically causing these changes and to what extent. And it is for this reason, among others, that I believe physicians should maintain epistemic humility regarding our preconceived notions of normal aging and assist our patients in making informed decisions about their care, even if we personally disagree with their approach. It is far safer for patients to be under the supervision of a trained and experienced physician, rather than falling victim to those looking to capitalize on their vulnerable ignorance.

Austin Momii, MD is a Behavioral Neurologist at the University of Colorado. His investigative work lies in exploring the role of the cerebrovascular system and neurodegenerative disease.