How Rapamycin Extends Lifespan (mechanism and implications) Discussion

True - and CR (for most of us) is really hard and greatly lowers quality of life, so I’m with you on that issue.

But - and the data isn’t really complete from what I’ve seen - it seems that fasting for 3 to 7 days may provide some benefits via autophagy that at least increases healthspan, but we have to be careful to not lose muscle.

Ah, a new research paper that seems to cover what I wanted to know in this area of autophagy:

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.

HTML version of the paper:

https://onlinelibrary.wiley.com/doi/10.1002/mco2.150

Ah… Here is the full PDF of the paper:

https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.150

Some interesting points:

3.1 Autophagy in cancer

Autophagy has long been considered as a double-edged sword in cancer. At the early initiation stage, autophagy acts as tumor suppressor via removal of potentially harmful cytosolic contents and damaged organelles, thereby avoiding cell injury such as DNA mutation. At the stage of progression, autophagy acts as a survival mechanism to sustain tumor viability under stressful microenvironment, which also contributes to therapeutic resistance. Therefore, in-depth understanding of the roles of autophagy during various stages of carcinogenesis and in tumor therapeutic responses will provide important therapeutic strategies to eliminate cancer cells, reverse drug resistance and prevent recurrence.

3.2 Autophagy in neurodegenerative diseases

Autophagy is essential for maintaining the homeostatic demands of neurons, both at the level of the central and peripheral nervous systems.172, 173 Based on the observations that neurodegenerative disorders occur in autophagy-defective mice, it has been hypothesized that autophagy defect is an important etiological factor for neurodegenerative diseases in humans. Pathologically, most neurodegenerative diseases are associated with accumulation of protein aggregates, including mutant α-synuclein in Parkinson disease (PD), Aβ and C-terminal fragments of the amyloid precursor protein (APP) in Alzheimer disease (AD), pathogenic mutant huntingtin (mHtt) in Huntington disease (HD), and mutant SOD1 (superoxide dismutase 1) as well as TDP-43/TARDBP (TAR DNA binding protein) in amyotrophic lateral sclerosis (ALS).172, 174 These protein aggregates are toxic drivers of neurological lesions and are supposed to be degraded by the autophagy–lysosome pathway.172 Consistently, gene mutations of autophagic receptors (e.g., SQSTM1 (sequestosome 1), OPTN (optineurin), NBR1 (neighbor of BRCA1 gene 1)) are closely associated with neurodegenerative diseases.175-177 As a result, modulating autophagy is believed to be a promising strategy for treating neurodegenerative diseases. For example, autophagy activation of the aggregating receptor SQSTM1 promotes the clearance of mHtt, insoluble tau, and Aβ42.178, 179 Conversely, inhibition of autophagy with 3-methyladenine (3-MA) results in accumulation of mHtt aggregates.180, 181 Here, we review the recent advances in understanding the pathogenesis of neurodegenerative diseases associated with defective autophagy and discuss the therapeutic interventions for these diseases via targeting autophagy.

3.3 Autophagy in metabolic diseases

Overnutrition and reduced energy expenditure, mirrored by aberrant activation of the trophic axis (e.g., insulin signaling), contribute to the development of metabolic diseases such as obesity, insulin resistance, and type 2 diabetes (T2D). Mechanistically, excess fat accumulation causes insulin resistance and elevated serum free fatty acid levels, leading to systemic lipotoxicity and β-cell dysfunction.268 In fact, autophagy responds to minimal oscillations in intracellular and extracellular metabolism, thereby maintaining a tightly regulated balance between the anabolic and catabolic pathways.269 For instance, the essential molecular players of cellular energy status, such as MTORC1 and AMPK, are involved in nutrient deprivation-induced autophagy. Autophagy performs inherent metabolic tasks in major organs such as adipose tissue, liver, and the exocrine pancreas and participates in maintaining energy balance in the body.270 As a result, dysregulated autophagic flux contributes to the pathogenesis and progression of metabolic diseases. In this section, due to space limitation, we will focus on the implications of autophagy in obesity and T2D.

MODULATION OF AUTOPHAGY AS THERAPEUTIC STRATEGY IN HUMAN DISEASES

As we discussed in the previous section, approaches modulating autophagy are demanded by its important role in human health and disease. Based on the intention of different clinical applications, both autophagy activators and inhibitors have been developed and tested in the past several decades (Figure 8). Here, we reviewed and grouped the known autophagy modulators in this section.

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So where does this leave us?
Is rapamycin not sufficient for autophagy?
Do we add things like melatonin and curcumin? Even add additional things?
But how do we know and what are we measuring?

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I think this is the article you referring to - it’s very good

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

https://www.nature.com/articles/s41467-022-29714-6

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I think cap-dependent and cap-independent translation of the mRNA also plays into longevity. Rapamycin, 7-alpha estradiol, acarbose, CR, fasting, and genetic longevity mutations all switch your body from cap-dependent translation to cap-independent.