One of the key issues we face is that while we know many compounds activate autophagy in some tissues, we don’t know where / what tissues, and how much. Also - while we know that autophagy is important and a good thing most of the time, we do not know the optimal doses or dose/response levels for all the different activities (e.g. fasting), drugs and supplements that activate autophagy.
Tim Sergeant was one of the lead researchers on the the area of measuring autophagy in blood, they were the first group to do this I think. Sadly, not yet available in any clinics anywhere, only in the lab. Here are their details and paper:
Although autophagic flux can be measured in humans using the methodology detailed in [8], the ultimate goal must be to identify a biomarker of autophagic flux. An autophagy biomarker would permit two significant advancements: (i) retrospective characterisation of clini- cal specimen collections and biobanks and (ii) technological developments to measure autophagy easily in a clinical setting. Clinical assessment of a patient’s autophagy will allow practitioners to provide interventions or advice to change it to promote healthy ageing.
I think that, like anything else, it’s possible to have too much of a good thing, even autophagy. It might be that you can exceed the capacity of the lysosomes to keep up.
We need a lot of things for clinical translation. I don’t even know if a blood test will be a pan universal absolute target. Maybe there’s a magical Sirolimus dose/time curve (several blood tests) that is the golden key? Perhaps another blood marker tagged back to some “gate keeper” tissue/signal?
As an engineer (Peter Attia is also an engineer btw, he thinks like one), one of our mantras is “you cannot manage what you cannot measure”. Let alone know WHAT things to measure and WHY?
He laments about this with Rapamycin as an intervention, and agree this is where we are.
But I’m not deterred, will continue to try and hardness some benefit. There is no do over.
Indeed. The human body is exquisitely designed for homeostasis. We see from chronic rapmaycin administration mTOR and autophagy become uncoupled leading to feedback loops and resistance.
Carcinogenicity risk associated with tacrolimus use in kidney transplant recipients: a systematic review and meta-analysis (2022)
“Currently, tacrolimus is the preferred anti-rejection therapy for kidney transplant recipients due to its greater protection against acute rejections compared to cyclosporin. The results showed a significantly increased risk of overall malignancy associated with tacrolimus exposure compared to non-tacrolimus therapy [risk ratio (RR) =1.59,and especially with sirolimus (SRL) (RR =2.58. The data demonstrated that patients treated with tacrolimus had a higher risk of carcinogenicity compared to patients treated with SRL”
Too much mTOR inhibition, or triggering other negative feedback cancer loops? Depressing tumour suppressor genes? Dissociating mTOR2, as TOR1/TOR2 have a cross talk, feedback loop?
I don’t know much about it. It shows that rapalogs aren’t all created equal. Is it a more potent immunosuppresant? Are NK cells suppressed? Maybe one of the mechanisms that you proposed.
another good, new, paper on autophagy for those who want to understand the area better:
Autophagy in health and disease: From molecular mechanisms to therapeutic target
Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome–lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington’s disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.
Another thought is combination of rapamycin with lithium for additional autophagy.
ABSTRACT
We recently showed that lithium induces autophagy via inositol monophosphatase (IMPase) inhibition, leading to free inositol depletion and reduced myo-inositol-1,4, 5-triphosphate (IP3) levels. This represents a novel way of regulating mammalian autophagy, independent of the mammalian target of rapamycin (mTOR). Induction of autophagy by lithium led to enhanced clearance of autophagy substrates, like mutant huntingtin fragments and mutant α-synucleins, associated with Huntington’s disease (HD) and some autosomal dominant forms of Parkinson’s disease (PD), respectively. Similar effects were observed with a specific IMPase inhibitor and mood-stabilizing drugs that decrease inositol levels. This may represent a new therapeutic strategy for upregulating autophagy in the treatment of neurodegenerative disorders, where the mutant protein is an autophagy substrate. In this Addendum, we review these findings, and some of the speculative possibilities they raise.
Perhaps good news on accelerating the process of identifying the best compounds for stimulating autophagy, and identifying optimal autophagy levels (by tissue type?) for longevity:
Tim Sargeant: Part of the reason you age is the accumulation of damaged molecules in the cells of your body. And these damaged molecules can build up, especially in the brain, and stop your brain from working properly, and this can lead to diseases that cause dementia. Autophagy is a process that prevents this from happening. We published a paper showing that autophagy works really hard all the time inside of human neurons, nerve cells, to degrade tangles that cause Alzheimer’s disease.
Norman Swan: What causes a failure of autophagy?
Tim Sargeant: We know there’s a genetic component. We know that Alzheimer’s disease, for example, is genetically linked to variation in genes that contribute to autophagy. We’re actively researching lifestyle factors that could contribute to a decrease in autophagy. So we’re looking at things like high fat diet feeding, and obesity, for example. But it’s also widely known that exercise can increase autophagy. And we believe that’s a part of why exercise is so beneficial as you age.
Norman Swan: In Alzheimer’s disease, you get the accumulation of these two proteins, beta amyloid and tau. People argue that these are just side effects of Alzheimer’s, not the cause, which is why the drugs aren’t very effective, if they’re effective at all. So you argue there’s something sitting behind that in Alzheimer’s disease.
Tim Sargeant: That’s absolutely correct. These molecules, amyloid plaques and tau tangles that accumulate on the insides of neurons, accumulate because of a defect in clearance. Amyloid plaques are born because neurons no longer efficiently clear waste through this process called autophagy.
Exercise, especially when high intensity, seems to be one of the most potent activators of autophagy, and also much more potent than overnight fasting.
Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation
