Cellular senescence is a state of stable cell cycle arrest associated with macromolecular alterations and secretion of proinflammatory cytokines and molecules. Senescent cells can affect every function in the body. Autophagy is process by which a cell breaks down and destroys old, damaged, or abnormal proteins and other substances in its cytoplasm (the fluid inside a cell). Senolytics step up the game in that whole dysfuctional cells can be eliminated.
Professor Robert Lusting explaining autophagy.
The tight connection existing between autophagy and aging is testified by several model organisms, where prolonged lifespan typically correlates with enhanced activity of autophagy and relative regulatory pathways.
One of the key drivers of aging is cellular senescence, a state of irreversible growth arrest induced by many pro-tumorigenic stresses. Senescent cells accumulate late in life and at sites of age-related pathologies, where they contribute to disease onset and progression through complex cell and non-cell autonomous effects.
Pharmacological treatments have been shown to extend lifespan through activation of autophagy, indicating autophagy could be a potential and promising target to modulate animal lifespan.
An essential process to maintain cellular homeostasis and functions, autophagy is responsible for the lysosome-mediated degradation of damaged proteins and organelles, and thus misregulation of autophagy can result in a variety of pathological conditions in human beings.
The failure of autophagy with age can be a very important aggravating factor in many diseases. Autophagy may provide an explanation why those suffering from Alzheimer’s or Parkinson’s also have other diseases. Autophagy failure leads to fat deposits and other garbage accumulation in the brain. Failure of autophagy in the brain affects other organs. Centenarians have better autophagy.
Calorie restriction mimetics such as spermidine activate autophagy. Macro autophagy is activated after maybe 2 hours without food, but chaperone-mediated autophagy (CMA) kicks in after 16 hours without food. Exercise also triggers chaperone-mediated autophagy via ketone bodies.
Main physiological roles of CMA (chaperone-mediated autophagy).
Experiments in mice have shown the beneficial impact of maintaining CMA for healthspan and longevity.
FIGURE 4. Common hallmarks of aging and cancer regulated by CMA. Recent evidence demonstrates that physiological aging and ND are associated with CMA downregulation, whereas glioblastoma (GBM) presents an upregulated activity. Processes regulated by CMA are represented in the figure.
Diminished CMA is associated with Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease, and other neurodegenerative disorders.
In most cells, chaperone-mediated autophagy (CMA) participates in protein quality control by degrading oxidized and damaged proteins under stress conditions and also contributes amino acids through degradation of proteins at advanced times of starvation.
Intermittent fasting for Increased Autophagy
Mice fasted for 48 hours (equivalent to 120 hours (÷2 X 5) in humans) showed a dramatic upregulation in neuronal autophagy.
This study of 11 overweight adults found that when they only ate between 8 am and 2 pm (early TRF (eTRF) they enjoyed decreased mean 24-hour glucose levels and reduced glycemic excursions. In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene SIRT1 and the autophagy gene LC3A, while in the evening, it tended to increase brain-derived neurotropic factor and also increased the expression of MTOR, a major nutrient-sensing protein that regulates cell growth.
This study of 625 healthy volunteers identified 367 genes in adipose and 79 in skin whose expression levels were associated with hours of fasting conditionally independent of time of day and season. Fasting-responsive genes were enriched for regulation of and response to circadian rhythm. We identified 99 genes in adipose and 54 genes in skin whose expression was associated to time of day; these genes were also enriched for circadian rhythm processes.
Autophagy happens while we’re sleeping—because that’s when we’re fasting. “If you eat a 30-inch pizza before bed, you’re not going to have any autophagy,” Dr. Gottlieb says. “That means you’re not going to take out the trash, so the cells begin to accumulate more and more debris.” Dr. Satchin Panda says, in this video, that a beneficial amount of autophagy does happen due to as little as 12 or 16 hours of fasting. Here is a supporting paper by Dr. Panda.
Chronic sleep deprivation impairs learning and memory, autophagy and neuronal apoptosis in mice.
Senescence not only prevents the proliferation of damaged cells, thereby preventing tumorigenesis, but also affects the microenvironment through the secretion of pro-inflammatory cytokines, chemokines, growth factors, and proteases, a feature termed the senescence-associated secretory phenotype (SASP). The SASP from accumulated senescent cells is thought to cause chronic inflammation that may contribute to many human diseases including cancer.
It is recognized that senolytics may delay, prevent, or even reverse the process of senescence and contribute to health span and even lifespan (17–19). In another line of action, senomorphics indirectly impair the senescence process, acting as senescence-associated secretory phenotype inhibitors, dissociated from the process of cell killing (18, 20). In the first category, we highlight Quercetin, Fisetin, Piperlongumine, and Curcumin; and in the latter one, Resveratrol, Kaempferol, Apigenin, and Epigallocatechin gallate (EGCG) (16, 21).
Senolytics including quercetin and fisetin have been shown effective at decreasing senescent cells in humans. Senolytic interventions not only demonstrated the feasibility of extending healthspan but also evidenced the alleviation of a wide range of pre-existent age-related symptoms including: improved cardiovascular function, reduced osteoporosis and frailty [26]; enhanced adipogenesis, reduced lipotoxicity and increased insulin sensitivity [27]; improved established vascular phenotypes associated with aging and chronic hypercholesterolemia [28]; as well as radioprotection and rejuvenation of aged-tissue stem cells [29].
The evidence on the senolytic effect of exercise on senescent cells in humans and animals appears convincing.
Autophagy promotes muscle tissue regeneration. Senescent cells inhibit muscle tissue regeneration.
There is compelling evidence that, at least in model organisms autophagy protects against diverse neurodegenerative diseases by decreasing the population of senescent cells. and proteins. Autophagy is critical for neuronal survival. Recent work in the field of Alzheimer’s disease has provided molecular and cellular evidence that links diminished autophagy to the pathogenesis of AD.
Senescent microglia are present in greater numbers in the brains of patients with neurodegenerative conditions. There is a role for autophagy in the clearance of extracellular Aβ fibrils by microglia. Autophagy is an essential catabolic process frequently failing in neurodegeneration.
Cellular senescence plays a direct role in chronic and age-related diseases and conditions, such as diabetes, atherosclerosis, neurovascular dysfunction, frailty, and dementias. Accumulation of senescent cells with aging contributes to multiple, age-related comorbidities that are frequently accompanied by neurodegenerative diseases, especially AD. Age-related declines in cognitive fitness are associated with a reduction in autophagy, an intracellular lysosomal catabolic process that regulates protein homeostasis and organelle turnover.
In rats it has been shown that preserved cognition was associated with the removal of peripheral senescent cells, decreasing systemic inflammation that normally drives neuroinflammation, blood-brain barrier breakdown, and impaired synaptic function.
Autophagy not only promotes waste clearance in the brain, but also alters cognitive abilities by changing the efficiency of the intracellular transportation system.
Autophagy provides better regulation of neuron calcium levels.
The hippocampus has a distinct circadian rhythm of autophagy that can be altered by sleep fragmentation.
Obesity causes a massive increase in senescent cells. Exercise can reduce the burden of senescent cells. This meta-analysis of 26 studies showed that physical exercise probably regulates autophagy in an exercise modality- and tissue-dependent manner in humans
Autophagy is up-regulated by calorie restriction, via neuropeptide Y.
Melatonin promotes neuronal autophagy.
Oleuropein aglycone (from olives/olive oil) may benefit Alzheimer’s disease by promoting autophagy.
Sulforaphane induces autophagy through extracellular signal-regulated kinase activation in neuronal cells. Pretreatment with NAC (N-acetyl-l-cysteine), a well-known antioxidant, completely blocked this autophagy effect. Sulforaphane of cruciferous vegetables enhanced autophagy flux led to the protection effects against prion-mediated neurotoxicity, which was regulated by AMPK signaling pathways in human neuron cells.
Based on literature data, it is suggested that physical exercise can induce autophagy in the aged brain via multiple mechanisms. Exercise induces autophagy in peripheral tissues and in the brain. Exercise intensely in short bursts and allow sufficient time for complete recovery. Intense exercise works via hypoxia, which is a potent inducer of autophagy.
Stimulating mitophagy and optimizing mitochondrial function through exercise may forestall the neurodegenerative process of AD.
A high dose of Urolithin A positively impacts exercise-performance measures. An increase in mitophagy proteins in human skeletal muscle observed in parallel. Supplementation is safe and increases circulating levels of Urolithin A.
- Mitochondrial and cellular health
- Age-related conditions
- Metabolic function
- Gastrointestyinal homeostasis
- Acute diseases
Polyphenols may increase autophagy independent of urolithin A. Coffee contains polyphenols.
EGCG from green tea promotes neuronal autophagy. Tea polyphenols were observed to activate autophagy through various different mechanisms, including the mammalian target of the rapamycin (mTOR) pathway
Long-term intensive endurance exercise training is associated to reduced markers of cellular senescence in the colon mucosa of older adults.
Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1. Ketones may up-regulate neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; elimination of damaged mitochondria that overproduce superoxide, as well as clearance of protein aggregates that mediate neurodegeneration. Many people can go into ketosis between meals. So run on an empty stomach, especially after doing resistance training.
