In this blog-article, I will review Otin’s 9 hallmarks of cancer, (Section A) and thereafter, in a second Section, I will propose both critical reflections to the nine hallmarks and add five additional longevity markers or hallmarks that appear to be relevant for the goal of reaching supercentenarianism, or what may be called the achievement of an evolutionary designed human life span’s potential (Section B).
The Nine Hallmarks of Aging Identified by Lopez-Otin
López-Otin’s paper systematically catalogs the nine processes which cause us to age (called the hallmarks of aging), these are “genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.” (1)
López-Otin defined the hallmarks based on how well they meet specific criteria, such as a) a particular hallmark must manifest itself during normal aging; b) if researchers experimentally aggravate the hallmark it should accelerate aging and finally, c) preventing or blocking the hallmark should retard aging, resulting in increased lifespan.
López-Otin categorized the hallmarks of aging into three groups. (See the reference of his book below). The primary hallmarks of aging are the foundational causes of cellular damage. The antagonistic hallmarks of aging are also known as response hallmarks. Finally, the integrative hallmarks of aging are a result of the damage caused by the first two groups.
Primary Hallmarks of Aging
The primary hallmarks are also called the foundational hallmarks of aging. Except for epigenetic alterations and programmed telomere shortening, these hallmarks involve macromolecular damage to the components of the cell. The hallmarks are not independent, and one often impacts the others. For instance, epigenetic alterations can affect protein stability, contributing to the hallmark of aging known as loss of proteostasis.
Starting Point: Genomic instability
Genomic instability is one of the hallmarks of aging. DNA damage occurs all the time, and our cells have repair mechanisms to correct these errors. As we age, however, our repair mechanisms fail to correct this damage, and mutations accumulate, leading to aging and disease. Cumulative DNA damage leads to genomic instability, a foundational hallmark of aging.
The human genome contains 3 billion base pairs of DNA. Each of our cells takes a DNA damage hit at the rate of 10,000 or over molecular lesions per cell per day. Our bodies have DNA repair processes to catch these errors. However, as we grow older, our DNA repair systems become less efficient and unrepaired chromosome lesions slip through the cracks. These errors add up as we age, increasing the incidence of diseases such as cancer.
It’s not just growing older that can inhibit DNA damage. Our lifestyles can also hinder DNA repair, including factors such as disrupted sleep patterns or stressors such as chronic worry. Furthermore, some scientists suspect that yet to be discovered mechanisms are responsible for failing DNA repair, possibly an epigenetic clock.
Meanwhile, pending the determination of this “Epigenetic clock” we can help to restore the body’s homeostasis, that which will reinforce DNA repair mechanisms and then, we can start the Holistic disease reversal process. Not before.
There are many techniques that nuture these mechanisms, which need to be strong and coherent in order to repair, to be useful, especially with today’s double hydrogen bonds being blasted all sides, a phenomenon which also promotes debilitating diseases and early death. These techniques range from circadian medicine like proper sleep, to proper eating, proper drinking, proper exercing, proper waste disposal (bowel and gut medicine are important in any reversal strategy) etc, proper breathing, proper playing, proper praying, proper everything, including boosting levels of Vitamin D, Vitamin N, NAD, nicotinamides and some small amounts of organic garlic, rosemary and red wine . (See workshop)
Hallmark of Aging #2: Telomere Attrition
Looking very much like the plastic tips on the ends of shoelaces, telomeres are the protective caps on the tips of our chromosomes. They progressively wear down as we age, and telomere attrition is a primary hallmark of aging. Telomeres are repeated patches of DNA that maintain the stability of our chromosomes and protect our genetic data. Telomeres also act as a biological clock in our cells. Each time a cell divides, its telomeres get shorter, until the cell either undergoes a form of cell death called apoptosis or becomes senescent. Unfortunately, when telomeres wear away – due to aging or environmental stresses – our DNA becomes vulnerable to degradation. Shorter telomeres cause genomic instability and may contribute to developing cancer.
To repair telomere breaks, some of our cells use an enzyme called telomerase to rebuild the shortened ends. Our bodies have two types of cells: regular cells which have a limited lifespan and stem cells which are immortal or quasi immortal. the regular cells do not use telomerase, while the stem cells do.
Because the degradation of these protective caps is a primary hallmark of aging, geroscientists are looking at ways they can lengthen our telomeres to lead longer, healthier lives. In fact, using RNA therapy to lengthen telomeres, one doctor was able to extend the lifespan of human cells in culture. As a recent report on telomeres and telomerase shows, very little progress has been made in telomere therapy since the publication of The Hallmarks of Aging.
Hallmark of Aging #3: Epigenetic Alteration
Epigenetic changes are an important hallmark of aging and have received much attention lately. Researchers recently discovered epigenetic clocks that may control how we age.The epigenome is the master program which controls our genetic code. An epigenetic program makes a series of temporary changes to our genome, and runs the show by turning genes off or on, and controlling protein production in particular cells.
Our environment influences our epigenome and modifies it via epigenetic changes. As we age, our cells are continually under assault by toxins and other stressors which change the epigenome. These changes accumulate over time, and geroscientists have linked them to the dysfunction and decline we associate with aging. Epigenetic alterations can occur via changes in RNA interference, histone modifications, and more commonly, DNA methylation.
Fortunately, changes in the epigenome are not permanent, and theoretically, this hallmark of aging can be reversed. As Carlos López-Otin says in his landmark review,
“Unlike DNA mutations, epigenetic alterations are – at least theoretically – reversible, hence offering opportunities for the design of novel anti-aging treatments.” (2)
Since the publication of López-Otin’s report, the epigenome has been in the spotlight, because it may contain a clock which dictates the aging process. Just this past month, geroscientists discovered two human aging clocks, a genetic aging clock in the brain, and a master clock in the epigenome that controls aging in the body.
Since the publication of The Hallmarks of Aging, scientists have made significant progress in understanding the epigenome, but little progress developing potential therapies. The changeability of the epigenome, as well as the recent discovery of epigenetic clocks, makes this hallmark of aging a potentially druggable target. Geroscientists want to develop drugs that can reverse epigenetically-driven diseases and maybe the aging process itself, this way, they can have lots of money too. But the driving force seems to be dogma, recognition and greed seeking. In actuality, we already have the Epigenetic Solution, it’s called Happiness Medicine.
Hallmark of Aging #4: Loss of Proteostasis & Autophagy
The decline in the protein quality of our cells, called the loss of proteostasis, is a fundamental hallmark of aging. Our bodies have defenses against cellular stress. However, after decades of repeated assaults by stressors such as free radicals and other toxins, the proteins in our cells become damaged or misfolded. Toxins are a significant source of disease and aging. For example, researchers have shown that free radicals in polluted air are particularly toxic, contributing to multiple age-related diseases. For example, a major study published a few days ago in the Lancet medical journal attributes one of out every six premature deaths worldwide in 2015 to disease from exposure to environmental toxins in the air and water.
In younger cells, our autophagy housekeeping system clears out these unfolded proteins. However, in aging cells, our autophagy janitorial services degrade, and our lysosomes become less efficient at eliminating this cellular toxic waste.
Geroscientists finger the decline in autophagy as a significant contributor to disease and aging, making the loss of proteostasis a primary hallmark of aging. The damage accumulates over the decades, and the mechanisms responsible for maintaining proper protein composition begin to decline. Proteins lose their stability, autophagy quality-control processes start to fail, and misfolded proteins accumulate, in a process known as cellular garb-aging.
Misfolded proteins form aggregates which sometimes produce disease. Amyloid proteins are an example of such aggregates, and play a prominent role in neurological conditions such as Huntington’s, Alzheimer’s, and Parkinson’s disease. Maintaining protein quality control is essential to health, and geroscientists are looking at ways to improve autophagy. Misfolded proteins also produce chronic inflammation. In a vicious cycle known as inflammaging, this build-up of cellular garbage increases the production of pro-inflammatory chemicals in our tissues which generates chronic inflammation throughout the body. This chronic, low-grade inflammation further accelerates the aging process.
The Secondary and Compensatory Hallmarks of Aging
Also known as response hallmarks, the compensatory hallmarks are physiological changes which come about as a result of the primary hallmarks. If geroscientists can stop the primary hallmarks of aging, then, in theory, it would reduce these response hallmarks.
Hallmark of Aging #5: Deregulated Nutrient Sensing & Caloric Modulation
As humans grow older, metabolic changes lead to deregulated nutrient sensing, a compensatory hallmark of aging. We have multiple nutrient sensing pathways to make sure that our bodies take in just the right amount of nutrients – not too much, not too little. However, the accumulated decades of assaults damage our nutrient-sensing pathways.
In this perspective, metabolic activities can put stress on our cells as well. Too much food intake or the wrong nutrient composition causes our cells to age faster. As those who do not live a holistic lifestyle age, the hypothalamus also becomes dysfunctional, encouraging us to eat more than the body needs, leading to metabolic syndrome, obesity, and type 2 diabetes. To make things worse, obesity and diabetes provoke chronic inflammation which can further deregulate our nutrient-sensing systems.
Because metabolic pathways are intertwined with longevity pathways, geroscientists have focused on them in their search for anti-aging treatments. Calorie restriction continues to be a leading anti-aging intervention. Researchers have high hopes that calorie restriction and forms of intermittent fasting such as the fasting mimicking diet can extend human lifespan. As a report on the fasting mimicking diet (FMD) shows, researchers have demonstrated that the FMD leads to improvements in health biomarkers as well as weight loss.
More on ROS
Hallmark of Aging #6: Mitochondrial Dysfunction
As our cells age, the mitochondria start to lose their integrity due to the build-up of free radical damage. Degraded mitochondrial function leads to decline in our cells and tissues and an increase in a type of cell death known as apoptosis. Damaged mitochondria produce even more free radicals which damage the mitochondria even further, leading to a weakened body. This mitochondrial decline is especially noticeable in tissues with high energy demand such as the heart or the brain.
Since the publication of the Hallmarks of Aging, geroscientists have placed greater attention on the mitochondrial role in the metabolic changes of aging, with a special focus on mitochondrial sirtuins.
More on ROS and emf
Hallmark of Aging #7: Cellular Senescence
As our cells age, they lose their ability to divide and become senescent. Researchers define cellular senescence as the point at which our cells stop dividing due to damage or lack of supplies. When we are young senescent cells are thought to be cleared by the immune system, but when we are older, they stick around secreting inflammation-stoking molecules that damage our bodies further.
Because cellular senescence is an important hallmark of aging, geroscientists have developed compounds which clear senescent cells from the body. When fed to mice, these compounds called senolytics rejuvenated old mice, making them look and act like younger ones.
Since the publication of López-Otin’s paper, scientists have made tremendous progress in developing senolytics. As a recent report on senolytics shows, geroscientists have discovered seven compounds which clear senescent cells and slow the aging process. Several of these compounds are slated for clinical trials.
Integrative Hallmarks of Aging
The integrative hallmarks of aging incorporate the first two groups and ultimately lead to the functional decline we all observe in aging. If geroscientists can stop the primary and compensatory hallmarks of aging, then, in theory, it would have downstream effects in reducing the integrative hallmarks.
Hallmark of Aging #8: Stem Cell Exhaustion
As we age, our stem cells eventually lose their ability to divide, leading to stem cell decline as an integrative hallmark of aging. As our stem cells go into decline, our bodies are unable to replace the stem cells that have migrated, differentiated, or died. As a result, we show outward signs of aging and an increase in age-related disorders.
Stem cell decline comes about as the result of many of the other hallmarks of aging, including DNA damage, deregulated nutrient sensing, senescence, and other degrading processes.
Because stem cell exhaustion is an important hallmark of aging, geroscientists are working on attempts to rejuvenate stem cells with synthetic chemicals and high tech technology. However, most times, this leads to both drug resistance and significant complications and toxic effects.
Today’s modern medicine is not interested in avoiding the disease. Conventional medicine can’t survivre without the disease it creates and maintains. Conventional Medicine does more harm than good, the evidence supports this wild assessment beyond any reasonable doubt. To maintain and reinforce human Stem cells, the royal path is Holistic medicine, which is practically free, yet without the toxicity of conventional medicine. (See blog)
Supercentenarian lady lived with only two stem cells….develop
Hallmark of Aging #9: Altered Intercellular Communication
As our cells grow older, their communication with other cells becomes dysfunctional leading to an increase in chronic inflammation and unhealthy hormonal changes. The aging cells in the organs play havoc with the body, changing the quality and quantity of hormone instructions they transmit throughout the body. For example, the aging hypothalamus changes neurohormone signals, which in turn affects food intake and metabolism. Since the hypothalamus also regulates sleep cycles, these changes can inhibit DNA repair, accelerating aging even further.
As cells age, they increasingly produce inflammatory distress signals that damage other tissue. For example, senescent cells produce buckets of inflammatory compounds that damage the tissues. Geroscientists define inflammaging as the imperceptible chronic inflammation that accompanies aging. Inflammaging is persistent and low-level, unlike acute inflammation which is short and sharp. Inflammaging wreaks havoc throughout the body, increasing dysfunction and disease.
Researchers have made mercantile progress in this area, with the announcement of the successful allopathic clinical trials of a promising new drug called Canakinumab that, that claims to do what any healthy and or holistically trained body can do, avoiding heart attacks and cancers by dampening inflammaging or even eliminate it entirely, thanks to a genuinely holistic lifestyle and an anti inflammatory diet.
The Institute’s Proposal for Five Additional Hallmarks
10. Circadian aging pathway
11. Microbiome’s networking
13. The Thymus connection
14. Glycolysis versus mitochondrial fuel burning and cellular respiration
Many of the invoked mainstream anti-aging experiments were done with greed in mind, in order to find an anti-aging pill, which we call “senolytics” like metformin, which is presently being tested by the NIH as an anti-aging pill. ( ) The purported intent to “slash” cancer and chronic diseases in order to attain advanced aging without including holistic lifestyle change would appear to be inconsistent with the only human empirical evidence we have on supercentenarians and longevity zones.
Christian Joubert (OLI director
TEXT STILL UNDER CONSTRUCTION
Reference and Precision Notes
Carlos López-Otín, et al. The Hallmarks of Aging. (2013) Cell, Volume 153, Issue 6, 1194 – 1217. Available Online.
And while geroscientists have made progress in many areas in the last five years, the most significant accomplishment is that several anti-aging drugs have entered into clinical trials to test their lifespan-extending powers. These include the much-heralded rapamycin, the diabetes drug metformin, one senolytic drug combination and the NAD-boosting molecule nicotinamide mononucleotide (NMN).
Intermittent fasting is not for everybody. Researchers have identified several promising drug candidates that slow the aging process according to a recent report on the metabolic changes of aging
Start point is Energy entropy, all else manic