D. S. McGerk | August/2017
Topic: Autophagy - a New Science
Animal adaptation to Food Shortages
Autophagy - a New Science which for the last 30 years has been developing.
Professor Yoshinori Ohsumi pioneered this new science base on the work of other Nobel Prize winners on
Liposomes/Vacuolar System and the
The trail to cellular recycling of
Scarce Resource was being uncovered. When we consider that the normal state of man throughout evolution was
this implies that
Fasting is a Normal State, then
Eating is a Stress State.
(1,1a,b,c) (Note 1)
During starvation periods and lack of carbohydrate sources (seasonal), the formation of ketone bodies increases dramatically. Prolonged low levels of insulin result in both increased
fatty acid release from adipose tissue, and increased amounts of the enzymes required to synthesize and utilize ketone bodies. Ketone fuel is more efficient and has less waste by products. Animals store
they do not store
except for a limited
Fight or Flight Response.
In addition, it turns out we have a
Reutilization Process - Autophagy for protein recovery as micro-molecules and metabolites. (2,3,3a)
Proteins How Much | What should be dietary goals?
The last 30 years of the development of the science of autophagy, has shown the efficacy of animal metabolism to recover and utilize
The graph presented shows Prof. Ohsumi's analysis of protein reutilization and it is about 70% efficient since some damaged and folded proteins cannot be recovered.
(Note 3, Summary)
In the mid 1950's scientists observed a new specialized cellular compartment, called an organelle, containing enzymes that digest proteins, carbohydrates and lipids.
This specialized compartment is referred to as a "lysosome" [Nobel Prize, Christian de Duve] and functions
as a workstation for degradation of cellular constituents. Christian de Duve coined the term
Self-eating. The new vesicles were named autophagosomes. (4)
Dr. Ohsumi found that autophagy is essential to maintaining vital activities in the body as it recycles amino acids that are the building blocks for proteins inside the cell. It is thought that a malfunction with autophagy is a factor in disorders such as Parkinson's disease, and scientists are hoping that this research will lead to the development of preventative measures and new treatment methods.
Autophagy | A Process of Cellular Digestion and Recycling
Dr. Patrick's Interview about Autophagy with
Dr. Guido Kroemer on Autophagy, Caloric Restriction Mimetics, Fasting & Protein Acetylation - Jul/2017.
Autophagy is an evolutionally conserved intracellular process to maintain cellular homeostasis by facilitating the turnover of protein aggregates, cellular debris, and damaged organelles.
It is a process whereby cellular activity sequesters portions of the cell and digesting them. (5) This recycling takes this cellular material and degrades the macromolecules
into micro-molecules and metabolites. This is part of the cell's
Repair and Maintenance cycle.
Most readers understand
Apoptosis which is cell death, and a programmed mechanism, but
Autophagy and apoptosis work together to control the
turnover of organelles and proteins within cells. This Self-consumption of cells and cellular materials is an animal adaptation for capturing and reusing scarce resource. (6)
However, these two process are distinct self-destructive processes in that
Apoptosis, Self-killing and the other
Fig 2: From Dr. Ohsumi's Nobel Prize acceptance speech (1) - Autophagy and Reutilization of Protein amino acids. This science has now been connected to various physiological cellular functions (.ppt presentation - 70GoingOn100.)
This new science has gone from 20 published papers 30 years ago to over 7,000 last year alone. The two processes of
regulate cell death and cell recycling and seem to work in conjunction with cellular stress and aging.
Accumulation of intracellular damage is an almost universal
Hallmark of Aging.
An improved understanding of the systems that contribute to cellular protein quality control has shed light on the reasons
for the increased vulnerability of the proteome to stress in aging cells. Maintenance of protein homeostasis, or proteostasis, is attained through precisely coordinated systems that rapidly correct
unwanted proteomic changes. (7,8,8a,9) (Note 4, 5)
Autophagy and Aging | Declining autophagy Efficiency?
Autophagy and Aging - at last a primary focus of 70 Going On 100 and living to 100, i.e
becoming a Centenarian. Dr. Yen and Dr. Klionsky explain that autophagy is involved in aging ...
For example, the role of various hormones and nutrient sensing pathways in life span extension may involve autophagy. Similarly, autophagy is the primary mechanism for removing damaged organelles,
such as mitochondria, which may have a direct impact on aging. Autophagy, an evolutionarily conserved catabolic pathway in eukaryotic cells, plays an important role in stress response and the
degradation of damaged cytosolic components.
According to Dr.'s Yen and Klionsky - [How to Live Long and Prosper: Autophagy, Mitochondria, and Aging] (10)
- Aging cells gradually accumulate various deleterious changes, resulting in a decline in cellular function and eventually leading to cell death and disease. The accumulation of damaged macromolecules and organelles
is one of the most persistent changes in aging cells and is associated with the decline of different catabolic pathways.
Autophagy deficiency during aging has been proposed to be the main cause of this biological
waste accumulation. (12,13,14)
A prominent theory of aging holds that decaying of mitochondria,
Mitochondrial Dysfunction Dr. Mercola and Dr. Patrick | jan/2016,
(15,15a,b) is a key driver of aging. While it's not clear why our mitochondria fade as we age, evidence suggests that it leads to everything from heart failure to neurodegeneration.
DNA repair is the issue. Refs ... DNA - Repair, PubMed.
Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection, and cancer. mTOR is a critical regulator of autophagy induction, with activated mTOR suppressing autophagy, and negative regulation of mTOR promoting it. Autophagy provides energy through the turnover of intracellular proteins and organelles to guarantee rejuvenation and adaptation in various conditions. (16)
During nutrient deficiency, autophagy functions as a pro-survival mechanism; however, excessive autophagy may lead to cell death, a process morphologically
distinct from apoptosis. The accumulation of damaged macromolecules and organelles during aging occurs due to reduced autophagy activity and leads to reduced lifespan, (17)
i.e. we do not want junk and senescent cells collecting, re-cycling is needed. (18)
Example: we replace all blood cells, on average, every115 days (3 times/yr), that is approximately 300,000,000,000 (billion cells per day), - ref ... this site - Healthy Heart and Longevity.
Malnutrition is a form of
Stress on our bodies which everyone does intentionally or unintentionally. If we are not aware of our nutrition we will trigger
Dr. Ames' Triage Theory and our body will start to reallocate nutrients in favor of short term health.
(Example: it has been shown that Vitamin K goes to blood clotting first, before it is used in other enzymatic functions such as
clearing calcification of arteries.)
Atkins - of the Atkins Diet, was partially right, as low carbohydrates (CHO) is the best way to eat
to avoid the complications of Insulin Resistance and Chronic Inflammation.
However, Atkins did not understand the importance of controlling Proteins (Autophagy - Reutilization), and hence because of the
Fear of Fat, people replaced carbs with proteins.
Controlling proteins suppresses mTOR activation, in cells since it is a missing nutrient. [Sabatini, 2016] It has been shown that after the age of about 30, insulin becomes less of a growth factor and the protein “Leucine” (a Branch Chain Amino Acit - BCAA) becomes the control. [Dr. Layman, 2013 - Protein Balance] (Note 6)
The mTOR pathway is a part of the survival pathway of cell signaling that helps in cell growth and proliferation. It is the central component of a nutrient and hormone sensitive signaling pathway that regulates cell growth and proliferation. This pathway becomes deregulated in many human cancers and plays an important role in the control of metabolism and aging. (19,19a)
The cell has to sense the proper nutrient levels for growth, both macro and micro nutrients. The mTOR and IGF are primary growth regulating pathways. Dr. David Sabatini a leading researcher on growth pathways such as mTOR provides an - Advanced Lecture: Regulation of growth by the mTOR pathway | Dr. Sabatini Lecture Series, march/2013 and a follow up in 2016 with David Sabatini, PhD , MD , Growth By The mTOR Pathway | cell signaling technology inc, feb/2016
The most powerful stimulation of mTOR is excess proteins. The best drug to reduce mTOR signaling
to "Slow Aging" and the chronic diseases associated with it, is already available …
Avoid High Proteins!
- Guess What - all roads lead to Diet.
Key Knowledge: You are turning off your immune system with a poor diet. The body favors short-term survival over long-term health. This trade-off accelerates aging-associated diseases, such as cancer, cardiovascular disease, immune dysfunction, and cognitive decline.
High carbohydrate diets, that are also high in omega-6 fats, shut down and confuse the body’s own antioxidant defense genes which are far more powerful than any supplement you can take. Unrecognizble free radicals are created.
- One of the
Hall-marks of LCHFis protein control in that it recommends a medium intake. Dr. Ohsumi's work indicated this parameter is in balance with animal adaptations. Protein restriction is also a component of Dr. Longo's FMD - Fasting Mimicking Diet. His proposed prolonged fasting (5 days) should limit proteins below 10% of caloric intake, and increase carbohydrates. This falls in line with the
Cycle-In-Outof Fat Burning - Fat Adapted mode as suggested by Dr.'s Mercola, Pompa, and others. Staying in Fat-burning mode, i.e. running on ketones, does not need to be done at full time once you are Fat-Adapted.
- Our Take Away - is we put
Excess Proteins Consumptionin the same category as
Excess Carbohydratesboth place undue burden on our metabolism. (Note 1,2) Will we ever find that happy balance? Our metabolic pathways are always dynamic pathways, and rely on a minimum required amount of macro and micro nutrients, consequently, our cells have developed a mechanism for conserving scarce resources, since historical evidence shows that
Starvation/Fasting was the Normal State of Humans.
- Professor Ohsumi's discoveries led to a new paradigm in our understanding of how the cell recycles its content. His discoveries opened the path to understanding the fundamental importance of autophagy
in many physiological processes, such as in the adaptation to starvation or response to infection. Mutations in autophagy genes can cause disease, and the autophagic process is involved in several conditions
including cancer and neurological disease. Built upon the work of
The Nobel Prize in Chemistry 2003, Peter Agre, Roderick MacKinnon..
The Nobel Prize in Chemistry 2004, Aaron Ciechanover, Avram Hershko, Irwin Rose. (1,1a,b,c,d)
- The kidney is an ingenious apparatus for removing substances the body wishes to dispose of. In its windings (termed glomeruli), which function as a sieve, water, ions and other small molecules leave the blood as ‘primary’ urine. Over 24 hours, about 170 liters of primary urine is produced. Most of this is reabsorbed with a series of cunning mechanisms so that finally about one liter of urine a day leaves the body. (20)
- The word autophagy originates from the Greek words auto-, meaning "self", and phagein, meaning "to eat". Thus, autophagy denotes "self-eating". This concept emerged during the 1960's, when researchers first observed that the cell could destroy its own contents by enclosing it in membranes, forming sack-like vesicles that were transported to a recycling compartment, called the lysosome, for degradation. In a series of brilliant experiments in the early 1990's, Yoshinori Ohsumi used baker's yeast to identify genes essential for autophagy. He then went on to elucidate the underlying mechanisms for autophagy in yeast and showed that similar sophisticated machinery is used in our cells.
- Hall-marks of aging - There is accumulating evidence that ageing / aging, is associated with a progressive dysfunction of autophagy, a condition that may favor the accumulation of dysfunctional mitochondria, nuclear genome instability, stem cell attrition, enhanced loss of post-mitotic cells, immunosenescence, unwarranted inflammatory reactions and, in the end, the reduction of hormetic responses that is required for the adaptation to stressful conditions. Moreover, autophagy is induced by, and required for, the positive influences of longevity-extending regimens, including caloric restriction, inhibition of insulin and insulin-like growth factor signaling (IGF-1, IGF-2, IGFs, GH Axis), (21,22) [Wikipedia
- Protein function is generated and maintained by the proteostasis network (PN) (Balch et al. (2008) Science, 319:916). The PN is a modular, yet integrated system unique to each cell type that is sensitive to signaling pathways that direct development and aging, and respond to folding stress. Mismanagement of protein folding and function triggered by genetic, epigenetic and environmental causes poses a major challenge to human health span and lifespan.
- While most amino acids are broken down in your liver, BCAAs are broken down primarily in your muscle. As such, they're believed to help improve exercise performance as well as reduce the breakdown of muscle.
Exercise and Gene Expression
Three amino acids - leucine, isoleucine and valine, are considered branched-chain amino acids (BCAA) because they have a branched molecular structure. In particular, leucine is shown to "accelerate recovery from muscle damage by preventing excessive inflammation". (23,24) We discuss leucine as a factor in Protein Balance and Metabolism.