The Vicious Cycles of Aging

Today's open access paper is well worth reading through completely; the middle sections are a good consideration of how specific mechanisms and diseases in aging feed upon themselves to progress ever faster over time. Aging is a process of damage accumulation. The damage itself is comparatively simple; aging is complex because cellular biology is complex, not because its causes are complex. Consider rust in a baroque metal structure of many parts. Rust is very simple, but the way in which the structure falls apart over time is not simple. That is a function of the structure, not the rust. This is why I favor developing means to repair damage, as close to the root causes of aging as possible, rather than trying to adjust the operation of metabolism to resist the damage. Repair is an easier task, and should also be more effective when successful.

Anyone who has owned, used, and maintained machines has a good idea of the pattern of aging of any complicated system. Wear is slow at the outset, and then it accelerates into consequences and dysfunction quite quickly at the end of the machine's working life. Damage causes further damage, and different types of damage interact to produce a worse outcome than would be the case for either on its own. Aging is a feedback loop, an accelerating process of breakage causing further breakage. This is true in something as simple as a hammer. It is true in something as complex as our bodies, capable of self-repair.

Beyond the conclusion that addressing damage through repair is better than trying to compensate for damage, another obvious consequence of this view of aging is that prevention in the early stages is far better as a strategy than waiting until matters progress. Since damage spawns further, more complicated forms of damage, and the process accelerates, then it will be many times more costly and challenging to reverse later stages of aging. Start the repair therapies early. That is easier said than done in the present stage of development of rejuvenation therapies, of course. The first treatments worthy of the name are still uncertain, where they exist at all. Early treatment even with highly effective rejuvenation therapies means small benefits, hard to measure, and for most intents and purposes it will be indistinguishable from a treatment that didn't work at all.

Molecular mechanisms behind the rapid progression of age-related diseases

Statistical data indicate that the mortality rates due to all major age-related diseases increase exponentially with age. Researchers have hypothesized that the reason behind this self-aggravating disease progression is the indefinite repetition of reaction cycles, which increases the harm from the initially noncritical changes in the body manyfold. It is these cycles that prospective therapies might address. "Investigating the mechanisms behind age-related disease progression, one concludes that by the time the disease has been diagnosed, it is too late to address the triggering factors. Apparently the most effective strategy is to interrupt the known vicious cycles by blocking certain stages in them. Drugs doing just that are already being developed."

Researchers examined the mortality rates of patients with five most widespread diseases that tend to affect elderly people more often, leading these diseases to be widely regarded as age-related: atherosclerosis, hypertension, diabetes, Alzheimer's, and Parkinson's diseases. Mortality statistics are the most powerful and least biased tool for studying diseases, since they account for the natural progression of a disease under various life conditions across a large population. A detailed analysis of age-related diseases revealed that they progress exponentially due to reactions on the molecular or cellular level producing pathogenic products which in turn initiate the very reactions that produced them. That way the harmful products quickly multiply, and the disease progresses at an ever increasing rate, like an avalanche.

For example, nerve cells in the brain contain a small amount of a protein called alpha synuclein, which is involved in nerve impulse transmission. It may happen that the gene encoding alpha synuclein is mutated, duplicated, or triplicated in a genome. This leads to multiple protein molecules sticking to one another, forming so-called toxic oligomers, which then grow in size by attaching other alpha synuclein molecules. This process produces fibrils, which from time to time break up into oligomers, each of which eventually grows into a new fibril, etc. This chain reaction causes the number of toxic alpha synuclein oligomers to grow exponentially.

Age-related diseases as vicious cycles

Nationwide mortality and disease incidence statistics are perhaps the most powerful and least biased datasets on human diseases that we currently have. These data are derived from humans living in the complex environment and developing diseases naturally, and not from distantly related animals contained in laboratory conditions under disease-inducing regimens. I decided to use disease statistics to elucidate the underlying nature of five major ARDs: atherosclerosis, hypertension, diabetes, Alzheimer's and Parkinson's. As large-scale incidence data for these diseases is not readily available, I have instead evaluated the age distribution of mortality.

It can be seen that the exponential function provides a reasonable approximation for mortality from atherosclerosis, diabetes and Alzheimer's, but is inadequate for mortality from essential hypertension and Parkinson's. The slightly more complex but mathematically correct logistic function provides the fits that are at least as good as for the exponential function, and in addition provides the perfect fit for Parkinson's disease mortality. Finally, the sum of two logistic functions is required for the adequate fit to mortality from essential hypertension. This may indicate that essential hypertension is a heterogeneous disease composed of two major subtypes with different mortality kinetics.

This study showed that potential vicious cycles underlying ARDs are quite diverse and unique, triggered by diverse and unique factors that do not usually progress with age, thus casting doubts on the possibility of discovering the single molecular cause of aging and developing the single anti-aging pill. Rather, each disease appears to require an individual approach. However, it still cannot be excluded that some or all of these cycles are triggered by fundamental processes of aging, such as chronic inflammation or accumulation of senescent cells. Nevertheless, experimental data showing clear cause and effect relationships between fundamental aging processes and ARDs are still missing.

It could also be that the above-mentioned fundamental aging processes themselves are mediated by positive feedback loops. For example, chronic inflammation can amplify itself similarly to autoimmune diseases via cytokines and epitope spreading. Cellular senescence can propagate from cell to cell in a chain-reaction fashion via cytokines and reactive oxygen species. DNA damage may amplify by affecting the genes of more and more DNA repair enzymes. Accumulating intracellular garbage may impair the lysososmal function, leading to ever-accelerating garbage accumulation. However, to test these propositions, longitudinal data on the kinetics of corresponding processes should be obtained.

Comments

A car is always a simple analogy. For example "small benefits, hard to measure" equates to the regular servicing of one that's quite new. You're paying out for this and then driving it out of the garage wondering if the mechanic has actually done anything.

Posted by: Neal Asher at February 15th, 2019 2:26 AM

I am hoping it works the other way as well. That improvement in areas like senolytics and glycation cross-breakers, cause improvements in systems not directly related.

Posted by: aa3 at February 15th, 2019 3:39 AM

"This is why I favor developing means to repair damage, as close to the root causes of aging as possible, rather than trying to adjust the operation of metabolism to resist the damage. Repair is an easier task, and should also be more effective when successful".Agreed that repair is critical, and maybe the most difficult part, but identifying and fixing root causes is a must and fixing the processes between the root cause and the damage is also necessary. It is a very complex issue. Eg for Alzheimer's the common agent of damage seems to be ROS, the proximate cause is inflammation that produces ROS, the root causes of inflammation are numerous, including infection, stress, senescent cells, trauma, toxins and vitamin/micronutrient imbalances. Then there are enablers that increase the probability of a root cause being effective, like hormonal/vitamin/neurosteroid deficiencies. All must be addressed. Murray

Posted by: Murray Duffin at February 15th, 2019 12:54 PM

I agree with the rejuvenation approach as well. However, I am afraid that since Juvenescence is coming up with keto mimetic pill the money is simply down the drain. Everyone focuses on slowing aging but aging is an underlying process that happens since we are born, fixing fatal damage should be a priority.

Posted by: Dokuganryu at February 16th, 2019 3:54 AM

Stem cell therapy from your own purified fat cells is a relatively new healing therapy for repairing accident repair but aging as well. The medical practitioners simply inject the stem cell laden fat matrix into the back of the shoulder or knee or wherever the muscles or tendons are torn or damaged and they rapidly repair use of the shoulder or knee. In the case of aging repair and wellness, the stem cells are injected in the blood stream and accomplish tissue repair wherever needed. This is such a recent medical science that it has not been fully evaluated yet. I have been using NAD+ for repair of aging skin, and one of the things that NAD* does is reprogram aged adult stem cells and fibroblasts so that they are activated in the presence of SIRT1 and sirtuins such as resveratrol of pterastilbene. Since I have been using the NAD+ my skin on the back of my hands and fingers, and all the way up and including my shoulders has become years younger. I had torn shoulder muscles in my right shoulder from playing tennis 20 years ago, and have had some pain and lack of full motion since then. But since taking NAD+ my shoulder has completely healed. I attribute it to NAD+ reprogramming the adult stem cells in my shoulder and repairing the muscle/tendon damage.

Posted by: Biotechy Marcks at February 17th, 2019 6:50 PM

PS: I have looked at the 5 major ARD's and I have no apparent blood test, physical or genetic SNP characteristics of these diseases. I am 78 and have had my carotid arteries and abdominal areas scanned by ultrasound with no atherosclerotic plaques present. My blood pressure last week during my annual physical was 102 over 60, thus no hypertension problems. My Doctor looked at my blood tests, and commented that I would never get diabetes; he said he wished he had some of my results like HDL of 82. I also checked my DNA results from 23andme, and have no diabetes related SNP's. Also for AD, I have the APOE 2 form which is protective of AD. On Parkinson's Disease, I likewise have no bad SNP variants. Of course a lot of things can spiral out of control, so you must follow a healthy lifestyle, like plenty of exercise, great diet, and good rest and relaxation, and always keep up on the longevity literature.

Posted by: Biotechy Marcks at February 19th, 2019 2:48 PM

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