Insulin replacement isn’t quite that easy from my experience - that’s from speaking with many type 1 diabetics with an “artificial pancreas”. There’s always the nasty risks of insulin pump malfunctions and infection using these automated methods. Imagine doing that with the worry of bacterial infection risks when on rapamycin. I try to avoid infection sites as much as possible because I don’t want to be forced to resort to systemic antibiotics. I even tried a lot of different experimental vaccines (ie GBS is getting up there in bacteremia) just to avoid this issue.
If they are injecting it themselves - I’ve seen a good amount worry about getting it wrong, preferring to go hyperglycemic to avoid hypoglycemia. They aren’t usually able to afford enough physician time for optimal therapy.
As for levothyroxine - as far as I know, replacement in subclinical hypothyroidism is controversial and it is generally recommended not to start for those between TSH 5-10. Very weak recommendation for those who are TSH >=10, generally speaking. Generally avoided in older patients due to risks. The proposed health benefits of getting to “normal thyroid levels” in clinical trials haven’t really panned out from my understanding, but I’m not super up to date on the research for treating subclinical hypothyroid.
Sorry, not a “literal” easy, but less controversial for replacing. The risk of hyperglycemia to the point of DKA is usually not as controversial to replace insulin than just replacing a borderline lower testosterone level.
Symptomatic low thyroid is usually not a controversial replacement when labs meet the criteria of Hypothyroidism. The lab ranges you are using meet the standard definitions, but are losing ground with new information suggesting better health benefits of TSH levels less than 4 and many endocrinologist liking levels between 1-2, but that is getting into the more finesse ranges.
Sorry - all of that is off point. I was interested in your perspective in what mTOR regulation does differently in a young person vs. an older person? Younger people have many of the mTOR stimulators - higher IGF-1 and testosterone and older people have less of both.
Tough but good question. I don’t know all the aspects because it’s a field of ongoing research, from my understanding - more senescence cells, more resistance to starvation, harder to inhibit mTOR that way. There are many other things currently under investigation.
As far as rapamycin is concerned - I only came by this only a bit more than a year ago frankly with the ITP results that convincingly showed rapamycin is better at earlier than late for mice.
I am currently waiting for the dog aging project, as well as several of my own dogs from the shelter (very small n, but larger and older “healthy for their age” dogs with complete frequent blood tests) to get quicker results to compare with the Test of Rapamycin in Aging Dogs results in middle aged dogs
Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects
It might fit why younger and older people regulate mTOR differently.
High levels of senescence that we see more as we age may trigger a "stuck " mTOR signal. Instead of a the concept of gas (stimulation) and or brake (inhibition) it may fit better to think of being in different gears - so the aging process that creates more zombie cells makes mTOR stick in 1st gear - which creates inflammation and age related process from this stick. Using the gear analogy further, this may explain why using anything else that seems contrary to what would make sense in our current model of either “on and or off” could cause mTOR to unstick from what gear it is stuck in to have better symptoms noted.
Both Rapamycin and Testosterone seem to create better symptom results by opposing mechanisms - but if part of that mechanism is to just unstick mTOR from what “gear” it is in, then we may have a model that makes more sense and can manipulate better. I believe their are some similar models for hormones that use negative feedback loops with pulsed hormone releases to regulate.
I would worry about using testosterone for myself unless I have a clear indication.
For example, I actually have “high-normal” levels of serum testosterone. The problem I have is some patches of receptors may be less sensitive to testosterone as indicated by my medical genetics physician. The current testosterone replacement therapies as far as I know do not account for pharmacogenetics, let alone the epigenetics parts.
I do not have hypogonadism symptoms (nonspecific symptoms i.e. lower than average energy and sexual interest don’t really count but I don’t have those either) or fasting subnormal morning serum testosterone concentration on 2-3 separate occasions. And it’s hard for me or my endocrinologist to interpret the results at my current age on top of rapamycin use that can change testosterone levels on top of my baseline T being different than average. Once I start treatment it may be difficult to cut down because there could be a prolonged period of hypogonadism with the recovery of the pituitary-testicular axis - not to mention it can eventually result in spermatogenesis suppression and reduced testicular size (more higher, more frequent doses of rapamycin appear to do this too - my pure guess is it can be partly or fully reversible very early on - but with TRT? Hard to predict)
It is also basically impossible to get to “normal” serum testosterone with oral testosterone despite all the misleading marketing out there. Gels are not even that stable, only relatively more so. Then there’s the issue of prostate cancer (sometimes even at 40 for some people), breast cancer (in men it can rarely happen with age ~35 onwards but quite possible with well-known BRCA and/or TRT such that one would probably need to do “breast exams”, getting estrogen levels right in men is also a problem, from my experience few physicians would actually do or have even done a breast exam on a male patient - let alone a testicular exam which is very low in the first place - nearly nobody goes looking for these things by asking breast cancer family history in a male patient, even when it might be indicated - can’t even find a specific “well man” exam out there with an andrologist as opposed to a widely available “well woman exam” with a obgyn), the slow march towards nearly inevitable BPH accelerating, possible new onset sleep apnea (don’t screw with sleep), risk of thrombolytic disease (erythrocytosis), venous thromboembolism (in my case I am tall and some other genetics stuff, which is an additional risk factor), the possibility of increased CV risk, some have adverse liver issues (I’m prone to it genetically) etc etc… that’s just the start of it. Way too many pitfalls for my liking here personally when I could just keep my T up over time with lifestyle factors, which appears to be possible even with 100-year-olds.
There are just so many potential problems that a decent endocrinologist has to be really careful in patient selection, yet I guarantee you many people aren’t getting all the indicated tests in the first place, and there is a severe lack of regulation in compounding pharmacy bioidentical hormone products.
All good points! You at 30 years young and on such an excellent healthspan / longevity routine may not ever need TRT or at least not for 20 years. Many people that use TRT are compensating for poor health habits that have put them in a position of lower testosterone - example elevated insulin can levels can change your SHBG, which then in turn alters your testosterone levels. I saw no value in TRT until almost 50 y/o, but I also practiced diet, sleep and exercise religiously.
Normal testosterone levels are kind of out the window when talking about replacement (my opinion) Once you decide to alter your levels it is hard to compare to what your body does when its “normal”. This subject has more data than Rapamycin, but the clinical application is not much farther ahead. Everyone has an opinion. i prefer injections of smaller dosing over the pills and or creams. Pellets are a whole other world, but many make good arguments for them and I use them on occasion for the right patient. I referenced a Harvard Urologist below that helps clarify much of the concerns you listed including prostate cancer.
I am really interested in your experience using a medical genetic doctor. It would seem that this is a future paradigm shift in basic medical practice. If you have time to share what the process has been like and where it seems to be a benefit.
Again, always appreciate your unique insight that is enhanced with your computer back ground as well as not being so distant from med school / boards and basic academics that most of us have forgotten. My son just started a general surgery program and is enjoying being able to apply what years of training required him to go through.
Well, the first thing you need to do is make sure the medical geneticist you will eventually see won’t blow you off from talking research or you’re just seeing a genetic counselor only because of understaffing. Insurance likely won’t cover it unless you have an indication. The waiting list I recall was almost 2 years where I’m at but it probably varies around 1+ year. Economically, they are struggling to survive. Salaries are so low and nearly nobody is going for the fellowships (kind of like geriatrics where you get paid much less than a regular PCP after going into a 1-2 year fellowship such that getting a specific geriatrician with specific research and background is nigh impossible - heck some geriatricians just hide their fellowship credentials - Medicare hates paying geriatricians enough and it’s a slow way for the average graduate to pay ~$200,000-$400,000+college loans+lots of interest while being paycheck to paycheck for so long). I wish you luck in finding one that is familiar with rapamycin and all the other experimental therapies out there.
as far as potential adverse risks such as prostate cancer and CV risks go when we are talking specifically about true hypogonadal men (there is a lack of documentation of whether hypogonadism was correctly diagnosed or actually there previously, then there’s the issue of intermittent, supraphysiologic T from injections etc etc):
(1) there is an absence of data from large, prospective, RCTs, especially with those prone to prostate cancer or existing prostate cancer, as far as I checked last time, so can’t say for sure guaranteed. The guidelines I last checked were must reevaluate for prostate cancer pretty frequently - which includes the prostate exam. The JAMA article Dr. M cites that should be retracted I actually read, it is retrospective which is severely limited. The problem is in verifying diagnoses, indications for TRT, dosing, and serum T before and after with careful monitoring.
(2) there is conflicting evidence in CV risk, but the possibility is high enough that the FDA requires adding the possibility of increased risks of MI/stroke etc.
The problem with most U.S. universities is that you are paying for the subsidized sports programs, acres of grass that need mowing, huge sports facilities and God knows what else that has nothing to do with your medical education
Living in Germany was an eye-opener for me. Many of their better universities have little or no campuses other than the basic buildings.
Cost of a medical degree in Germany?
“Put your wallet away: Germany’s medical courses are free. This makes it one of the best places to go if you’re studying on a shoestring budget and can’t afford to roll out the big cheques for each semester. Instead, you can happily chug along, safe in the knowledge that you’re getting a fantastic, world-class education from one of the most intellectually rigorous countries on the planet. Beware, however, as a very good knowledge of the German language will probably be required and you’ll have to pass a series of preliminary tests to get onto the course where these linguistic abilities will keep you in good stead”.
I had an offer way back to basically get an interview (and probably likely get in based on my stats) at HKU medicine through a family friend for ~$1000 a year at a premier medical school for MBBS way back via non-JUPAS since the HK government covers a lot of the costs. I thought hard about it and turned it down. The problem is getting a residency here as an IMG.
In addition, I was not actually paying that much for the sports and stuff while in med school (as opposed to college) - the state was paying almost $100,000 per year per medical student for cutting-edge software, simulations, research tools, and lowly paid academic physicians (I’ve literally seen how they screw over them on FTEs because $100k per year per student is not enough to go around), etc, etc. My med school actually surprisingly lost a lot of money with medical students to maximize their education. I was getting a huge steal for value.
Here’s another problem - US medical research/expert density (and variety) vastly outpaces any other country with the UK as a distant second and pretty much all the high-impact research is in English. The UK is far past German medical research but the UK favors their own much more, just as in the US.
These network effects heavily translate into healthcare. I happen to know a few UK physicians who’d rather get their medical care (particularly surgery) here despite inconvenience and expenses. Not to mention, if they need cutting-edge cell-based/gene-based therapy, rich Europeans will literally only come here at MD Anderson (or MSK etc) paying $1,000,000+ to get it, not stay in their own home countries. While I am in support of single-payer overall (with some caveats) and we clearly have a fragmented broken healthcare system, many average Europeans don’t realize they can’t get certain things there, nor do they understand the healthcare tradeoffs very well.
Really depends on how you run the numbers. I’m just running the relevant ones for my situation and context.
China has the most publications and most filed patents, but I am quite hesitant to say China is even close to the current global leader in medical R&D, even though that seems quite plausible to eventually change.
China is really coming on strong with fundamental research, but typically, it’s just some nuanced repeat of US/EU research, or a deep dive down a narrow pathway. It’s typically NOT, as you say, original research. But the thousands of post docs trained at US/EU schools are coming back to China, and will eventually do original research.
You might be able to open this NYT link, but paper link below.
You Won’t Live Longer by Diet or Exercise Alone, Study Says
Sprawling new research showed that healthy eating and regular workouts do not, in isolation, stave off later health issues. They need to be done together.
"When comparing across physical activity and diet combinations, the lowest risk combinations consistently included the higher levels of physical activity and the highest diet quality score."
Most people know that working out and eating well are critical components of overall health. But a sweeping study published this week in the British Journal of Sports Medicine suggests that hitting the gym won’t counteract the consequences of consuming fat-laden foods, and mainlining kale can’t cancel out sedentary habits.
“Sensationalized headlines and misleading advertisement for exercise regimens to lure consumers into the idea of ‘working out to eat whatever they want’ have fueled circulation of the myth about ‘exercise outrunning a bad diet,’” the study authors wrote.
Research Pub:
Physical activity, diet quality and all-cause cardiovascular disease and cancer mortality: a prospective study of 346 627 UK Biobank participants
