While I agree with both authors, it’s a bit of a red herring here as cognitive issues aren’t really a symptom and not something I would consider cosmetic or related to testosterone. While valid I don’t think is as relevant here
The rate of physiologic aging is variable depending on genetics, epigenetics, and molecular biology. There is already a study in humans with advanced type 2 diabetes that shows that death and diabetic complications can be delayed by 8 years.
I agree that age is merely a surrogate biomarker, and an imperfect one at that, for the state of one’s physiological function. Just as one can “appear as stated age”, one can certainly appear younger or older than that age as well. We have all no doubt remarked that this patient is “great for 90”. The only way we can do that is to first have a stereotype for what 90 looks like.
As with all stereotypes, it is based on a generalization of “average”, but there can certainly be (sometimes even wide) variance from this point estimate. Nonetheless, that average does exist for a reason. “great for 90” is noteworthy because it does represent a significant deviation from the average, but this can occur without compromising the usefulness of that “average” reference point (sort of an exception that proves the rule).
The same could be said for other surrogate biomarkers, like BMI for instance. Not everyone of a certain BMI is in the same state of health, but a high BMI does generally connote certain things.
I remain appreciative of Dr. Cifu’s appraisal of TRAVERSE. Testosterone replacement in small amounts is “probably” safe for CV endpoints, if you accept more PE, numerically more AF, and remarkably poor compliance.
Both the original essay by Dr. Cifu and this essay by Dr. Momii touch upon the same confounding issues: what is "normal" (maybe "expectable" is the better word) in light of heterogeneity and time (a special case of heterogeneity).
It is hard to think that "treating" what is "normal" is really "medicine"? Is it?
But because heterogeneity of experience and genotype it is hard to tease out what is "normal" because our models remain primitive (if we are honest).
(Ironically, compared to most species our genetic variation is very low probably because we have no niche environment; we live everywhere oblivious to the environment which is also likely why are in danger of destroying it. The greatest source of genetic division is the presence or absence of the Y chromosome but that has tied us in knots - we both overstate and understate its importance.)
And the heterogeneity caused by the arrow of time is massive: just think about the fetus, the newborn, the 2, 5, 10, 15, 25, 40, 60, 75 and 90 year old.
Very few have carefully operationalized age bin choices ("Jenks optimizing" might be a start, Fisher, Walter. (1958). On Grouping for Maximum Homogeneity. Journal of The American Statistical Association - J AMER STATIST ASSN. 53. 789-798. 10.1080/01621459.1958.10501479, Jenks, G.. (1977). Optimal Data Classification for Choropleth Maps. and North, Matthew. (2009).A Method for Implementing a Statistically Significant Number of Data Classes in the Jenks Algorithm. 6th International Conference on Fuzzy Systems and Knowledge Discovery, FSKD 2009. 1. 35-38. 10.1109/FSKD.2009.319.)
Failure to rigorously operationalize "normal" and healthy under heterogeneity contributes to medicalization. Unnecessary medicalization is exactly the problem with "cosmetic medicine".
I appreciate Dr. Cifu even more for encouraging such interesting dialogue among professionals. Dr. Momii's column is valuable and well-argued - thank you both for your time and care.
Another facet to this for consideration is the fact that any intervention has side effects. I look at my mother-in law and her friends and contemporaries, all around 80 years old give or take 5 years. Most of them have spent their entire adult lives piling intervention upon intervention. I have this undesirable symptom, so I take this daily medication or have this organ removed, causing this other undesirable symptom which then requires a different intervention, and so on and so on. It's really a mess! My goal is to make it to the end of my life with as few medical interventions as possible and all my organs. 🙏
"is age the etiology of these changes, or are we observing neurocognitive sequelae associated with an accumulation of cerebral pathology?"
I would argue this line of thinking can be extended to just about every disease traditionally associated with aging. For example, one could argue that cardiovascular disease is merely the accumulation of atherosclerotic plaques in blood vessel walls, or that osteoarthritis is simply the accumulation of joint pathology (in this case cartilage degeneration).
In other words, aging is understood to be a "surrogate" for the accumulation of pathology over time.
That said, so long as we do not have readily available tools that can directly measure said accumulation, age will remain an invaluable surrogate.
The question ultimately becomes "Do we want to prevent the accumulation of pathology? And if so, to what end/extent?"
I think most people would answer "Yes, at least to some extent".
On the individual level the "some extent" can be tailored to one's own liking (and means). The difficulty comes in defining the "some extent" on a societal (public health) level and allocating resources accordingly.
Dr Cifu's original critique of the original NEJM study (no clear increase in cardiovascular (CV) events, but predicated on modestly supplemented, frequently discontinued testosterone therapy) is well taken, including his point that industry supported trials can be manipulated by design to generate favorable outcomes for the sponsors. A very analogous trial with initial funding by the NIH (alcohol consumption and CV outcomes) was dropped by subsequent NIH leadership after sober (ahem) reflection. https://www.nih.gov/news-events/news-releases/nih-end-funding-moderate-alcohol-cardiovascular-health-trial . To Dr Momii's points, healthy diet and regular exercise have a better track record for preventing erectile issues, fatigue, AND white matter changes in the brain, with successful aging into the 80s often following. But as US health care is currently organized and funded, where's the profit in THAT?
Jul 4, 2023·edited Jul 4, 2023Liked by Adam Cifu, MD
Having recently spent nearly 6 weeks inpatient for CAR-T treatment of recurrent NHL, I got a really close look and feel for the medicalization of various "symptoms" (independent of the cancer + treatment) as well as the inherent cruelty and borderline unethical processes of bureaucratic US healthcare as delivered at a major academic medical center. I just wrote a run-on sentence to agree with you: the key driver boils down to PROFIT.
Thank you. There is much to learn and correct misinformation.
While I agree with both authors, it’s a bit of a red herring here as cognitive issues aren’t really a symptom and not something I would consider cosmetic or related to testosterone. While valid I don’t think is as relevant here
The rate of physiologic aging is variable depending on genetics, epigenetics, and molecular biology. There is already a study in humans with advanced type 2 diabetes that shows that death and diabetic complications can be delayed by 8 years.
https://pubmed.ncbi.nlm.nih.gov/27531506/
Thank you for the link to this study.
I agree that age is merely a surrogate biomarker, and an imperfect one at that, for the state of one’s physiological function. Just as one can “appear as stated age”, one can certainly appear younger or older than that age as well. We have all no doubt remarked that this patient is “great for 90”. The only way we can do that is to first have a stereotype for what 90 looks like.
As with all stereotypes, it is based on a generalization of “average”, but there can certainly be (sometimes even wide) variance from this point estimate. Nonetheless, that average does exist for a reason. “great for 90” is noteworthy because it does represent a significant deviation from the average, but this can occur without compromising the usefulness of that “average” reference point (sort of an exception that proves the rule).
The same could be said for other surrogate biomarkers, like BMI for instance. Not everyone of a certain BMI is in the same state of health, but a high BMI does generally connote certain things.
I remain appreciative of Dr. Cifu’s appraisal of TRAVERSE. Testosterone replacement in small amounts is “probably” safe for CV endpoints, if you accept more PE, numerically more AF, and remarkably poor compliance.
Both the original essay by Dr. Cifu and this essay by Dr. Momii touch upon the same confounding issues: what is "normal" (maybe "expectable" is the better word) in light of heterogeneity and time (a special case of heterogeneity).
It is hard to think that "treating" what is "normal" is really "medicine"? Is it?
But because heterogeneity of experience and genotype it is hard to tease out what is "normal" because our models remain primitive (if we are honest).
(Ironically, compared to most species our genetic variation is very low probably because we have no niche environment; we live everywhere oblivious to the environment which is also likely why are in danger of destroying it. The greatest source of genetic division is the presence or absence of the Y chromosome but that has tied us in knots - we both overstate and understate its importance.)
And the heterogeneity caused by the arrow of time is massive: just think about the fetus, the newborn, the 2, 5, 10, 15, 25, 40, 60, 75 and 90 year old.
Very few have carefully operationalized age bin choices ("Jenks optimizing" might be a start, Fisher, Walter. (1958). On Grouping for Maximum Homogeneity. Journal of The American Statistical Association - J AMER STATIST ASSN. 53. 789-798. 10.1080/01621459.1958.10501479, Jenks, G.. (1977). Optimal Data Classification for Choropleth Maps. and North, Matthew. (2009).A Method for Implementing a Statistically Significant Number of Data Classes in the Jenks Algorithm. 6th International Conference on Fuzzy Systems and Knowledge Discovery, FSKD 2009. 1. 35-38. 10.1109/FSKD.2009.319.)
Failure to rigorously operationalize "normal" and healthy under heterogeneity contributes to medicalization. Unnecessary medicalization is exactly the problem with "cosmetic medicine".
I appreciate Dr. Cifu even more for encouraging such interesting dialogue among professionals. Dr. Momii's column is valuable and well-argued - thank you both for your time and care.
Another facet to this for consideration is the fact that any intervention has side effects. I look at my mother-in law and her friends and contemporaries, all around 80 years old give or take 5 years. Most of them have spent their entire adult lives piling intervention upon intervention. I have this undesirable symptom, so I take this daily medication or have this organ removed, causing this other undesirable symptom which then requires a different intervention, and so on and so on. It's really a mess! My goal is to make it to the end of my life with as few medical interventions as possible and all my organs. 🙏
Same.
Dr. Momii's comments and perspective are just so, well...sensible!
"is age the etiology of these changes, or are we observing neurocognitive sequelae associated with an accumulation of cerebral pathology?"
I would argue this line of thinking can be extended to just about every disease traditionally associated with aging. For example, one could argue that cardiovascular disease is merely the accumulation of atherosclerotic plaques in blood vessel walls, or that osteoarthritis is simply the accumulation of joint pathology (in this case cartilage degeneration).
In other words, aging is understood to be a "surrogate" for the accumulation of pathology over time.
That said, so long as we do not have readily available tools that can directly measure said accumulation, age will remain an invaluable surrogate.
The question ultimately becomes "Do we want to prevent the accumulation of pathology? And if so, to what end/extent?"
I think most people would answer "Yes, at least to some extent".
On the individual level the "some extent" can be tailored to one's own liking (and means). The difficulty comes in defining the "some extent" on a societal (public health) level and allocating resources accordingly.
Dr Cifu's original critique of the original NEJM study (no clear increase in cardiovascular (CV) events, but predicated on modestly supplemented, frequently discontinued testosterone therapy) is well taken, including his point that industry supported trials can be manipulated by design to generate favorable outcomes for the sponsors. A very analogous trial with initial funding by the NIH (alcohol consumption and CV outcomes) was dropped by subsequent NIH leadership after sober (ahem) reflection. https://www.nih.gov/news-events/news-releases/nih-end-funding-moderate-alcohol-cardiovascular-health-trial . To Dr Momii's points, healthy diet and regular exercise have a better track record for preventing erectile issues, fatigue, AND white matter changes in the brain, with successful aging into the 80s often following. But as US health care is currently organized and funded, where's the profit in THAT?
Ohh, that pun, so good.
Having recently spent nearly 6 weeks inpatient for CAR-T treatment of recurrent NHL, I got a really close look and feel for the medicalization of various "symptoms" (independent of the cancer + treatment) as well as the inherent cruelty and borderline unethical processes of bureaucratic US healthcare as delivered at a major academic medical center. I just wrote a run-on sentence to agree with you: the key driver boils down to PROFIT.
Well stated. After all, every person we are privileged to meet is distinct and deserving of being treated that way.
Very wise points, thank you for sharing Dr. Momii's input.