Thank you very much Hieon for your thorough response. I appreciate the time and thought you put into this; made even more meaningful by virtue of your background in the field.
Please do not be offended by anything I express below, because I truly desire a productive and fruitful exchange on this site. We have nothing to gain from pure conflict and all that I write below is backed by a spirit of cooperation -even if I do a bad job of communicating that at times...
1. I'm just Bio MSc grad in med school currently and not a practitioner so I'm not gonna make personal recommendations or name all the alternative triggers of the same pathology, because I don't wanna be responsible for anyone's irresponsibility of simply buying or trying something just because "This guy said this". You can research yourself more or look for human vivo trialed drugs such as dasatinib of the similar modular inhibition of ALK5.
2. Everything in our biology has a mechanistic function. Even amyloid or tau tangles or TNF-alpha or cellular senescence all have their functions given their optimum level at homeostasis. Inflammatory response is also a defense mechanism, same applies to TGF-ß. These aspects are bad when they accumulate more than homeostatic level or artificially deregulated.
Therefore if TGF-ß signal is overexpressed particularly in aged mice, it makes sense to bring it down to optimum level through ALK5 inhibition, and this is the primary reason for investigation. But if you are at an optimum level already, and you downregulate it for whatever reason, then it will cause an inverse effect. That's why this is a rejuvenation tactic in the aged model, not a preventative tactic for healthy model.
Perhaps a contributing reason why metformin produced a lifespan increase in obese individuals but not proven in healthy individuals. Because their overall mechanisms are deregulated, metformin will bring them to homeostatic levels so improving overall healthspan. However in healthy folks, overactivating AMPK or overinhibition of mTOR will do no good or cause inverse effect because same reasoning applies; mTOR has its function as a growth regulator and should not be always inhibited, and only an idiot would think inhibition of any pathology is always good.
That's why if you make a knockout mouse of any of these will die instantly. All the investigative senolytics have other potentiating factors than just inhibition/activation, that is why it is still unclear how even metformin actually works.
So bottom line, there are alternative ways to induce ALK5 inhibition, but inhibition alone isn't what is giving off benefits from whatever compound. And if you think just inhibiting something will always be good, then you are no different than a druggy following hypes with zero understanding.
All that being said, I could be just as wrong as anyone. So do your own research and be skeptical please.
You are making so many assumptions; so to make this discussion more productive I kindly request that you refrain from assuming.
"I'm not gonna make personal recommendations"
Please; nothing at all that anybody wrote anywhere in this thread can be construed as asking for personal recommendations, who ever asked you for that?
" if you think just inhibiting something will always be good"
When did I ever express anything remotely resembling this? Not in any way, shape or form
"You really think mice model is directly translatable? "
Who ever said directly translatable. I even was the one who said in such experiments the safety of mice is a non-concern and we should take steps accordingly.
Every single time we take an action in life, we assume a risk. Hoping into your car to go to Starbucks constitutes a great risk. The number of people killed while driving and through no fault of their own is what... millions maybe since the invention of the automobile? However, if the risk is acceptable and we have already taken all possible precautions, we just have to move on
"because I don't wanna be responsible for anyone's irresponsibility of simply buying or trying something just because "This guy said this"."
If this is your mindset, this whole anti-aging thing is a non-starter really. If you go ahead and say, for example: "to accomplish the same end goal with fewer side effects, substance X makes more sense than ALK5-i. But this is not tested in humans and I do not deem self-experimentation a viable alternative" than you're good to go in my humble opinion.
If someone goes out and tries said substance based on such a harmless sentence that has been written on a discussion forum as part of an intellectual discussion, consequences are entirely and I mean entirely, their responsibility. If we are going to be this concerned with such individuals misusing the information herein, we really cannot talk on an open forum. People do wrong things and hurt themselves all the time. We cannot take every step in our lives with the primary goal of preventing such harm caused by others to themselves. We'd be betraying ourselves if we do so and would thereby allow such individuals to hurt us and society at large far more than they would (or will anyway despite our best efforts) hurt themselves.
"You can research yourself more or look for human vivo trialed drugs such as dasatinib of the similar modular inhibition of ALK5."
Sure I can research myself and I am. I can also produce a primitive shoe to wear and make a terrible bread to eat. However we chose to join our efforts to benefit from each other's accumulated wisdom. No matter how much I research, I will not become as wise in these said drugs as the combined wisdom of the people viewing this thread.
Not sharing our wisdom just because someone may do something extremely stupid and harm themselves as a result would be a shame.
If that will be our approach, why bother hanging out on a discussion board?
We simply cannot operate under the assumption that nature has optimized everything
"Everything in our biology has a mechanistic function. Even amyloid or tau tangles or TNF-alpha or cellular senescence all have their functions given their optimum level at homeostasis. Inflammatory response is also a defense mechanism, same applies to TGF-ß. These aspects are bad when they accumulate more than homeostatic level or artificially deregulated."
I disagree with the spirit expressed in the above comment and here is why:
The only way I can interpret the above is: "A 60 year old individual with no specific disease should not go in and do something to reverse or slow down aging". The very results we observe suggest -NOT THEY ARE NOT CONCLUSIVE AND YES THERE IS YET INSUFFICIENT HUMAN DATA, HENCE I SAY "SUGGEST" - that we can take a 60 year old who is in excellent shape for his age and has no specific disease, and remove some amount of the senescent cells in his body to make him function better. No, in the case of such an individual the amount of senescence in his body is not optimized by nature -we can do better by fine tuning it. Do we have the mechanism at hand for this? No. Do we know which cells to remove and how many of them to remove? No. Could it turn out that we are wrong and that removing even one single senescent cell by way or exogenous intervention will do more harm than good? Weeeellll, that last question is where it's at. One has to say Yes since we can never be certain and there is a very low probability here, but there is a very strong possibility that the more suited answer is No. It appears that probably removing some senescent cells will do more good than harm, but the "some" here is yet to be defined.
At the end some people like myself want to take such risks and others do not, and that is perfectly fine. We all have different priorities as well as risk profiles, which makes the world an interesting place...
To make matters all the more viable in this particular case, the very ALK5-i used in the mice study is referred to as FDA-approved. But, as you will see in the earlier posts, we could not figure out when / where etc.... However, at least it seems (SEEMS) that we are talking about a substance that at some dose won't outright kill you.
With all of that said, I would like to very respectfully submit the following questions:
1- What other more feasible alternatives may be worth intellectually discussing here other than the specific ALK5-i mentioned in the study? You did mention Dasatinib; anything else?
2- Would you speculate that the impact of those other ALK5-inhibitors too would possibly be boosted by adding Oxytocin?
Thank you very much for your input and, more crucially, your understanding.