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INTRINSIC DAMAGE AND THE HUMAN MAINTENANCE SYSTEM

 

“When scientifically investigating the natural world, the only thing worse than a blind believer is a seeing denier.”

Neil deGrasse tyson

 

The current aging paradigm is based on the assumption that the default state of a complex organism is to remain alive. By contrast, the New Paradigm observes that the default state of all matter, including living organisms, is to be inanimate, i.e., dead. The New Paradigm highlights the significance of two countervailing forces that have hitherto received little attention from conventional academicians – intrinsic damage and the human maintenance system. Regardless of any extrinsic factors, the cells and other biological components that make up the human organism have very short lifespans – frequently measured in days. The intrinsic damage that results from that constant dying off of biological components (and less than perfect replacement thereof) is an inexorable force that has afflicted every complex metazoan that has ever existed on the planet.

The infliction of intrinsic damage is inevitable, but it is not necessarily a problem; it is only when that damage accumulates that there is a diminishment in functionality. The critical countervailing force is the maintenance system, which is made up of a number of different maintenance processes that remove and replace damaged components at every level of biological organization.
The New Paradigm argues that the human maintenance system should be acknowledged to be a critical physiological system. It’s remarkable that, for the most part, the maintenance system has been ignored by academicians and scientists, even though aging theorists have long acknowledged that the accumulation of damage that results from inadequate maintenance is the critical issue when it comes to biological aging.

Intrinsic Damage

 In a 1957 article, evolutionary biologist George C. Williams wrote: “It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed.”(1)  In 2007, biogerontologist Aubrey de Grey wrote that the infirmities associated with aging are paradoxical because “it seems obvious that the maintenance of a complex machine in a fully functional state is a vastly simpler problem than the construction of that machine, so evolution, having mastered the latter, should find the former a doddle.”(2)

These quotations highlight perhaps the most fundamental misconception of the aging paradigm. Aging theorists have historically viewed complex organisms as akin to machines. Once one is fully developed, it’s assumed that, left to its own devices, it should be simple to maintain itself indefinitely. As a result, aging theorists tend to ignore the significance of maintenance systems. Instead, they focus on identifying the types of damage to biological components that maintenance processes appear to be incapable of preventing.(3)

The critical hidden assumption/misconception is that the default or natural state of an organism and its components is to live indefinitely, subject only to wear and tear or entropy.(4) That’s simply wrong.

Kuhn used the duck-rabbit optical illusion, made famous by Wittgenstein, to demonstrate the way in which a paradigm shift could cause one to see the same information in an entirely different way.

The gestalt shift called for by the New Paradigm involves the acknowledgement that the default state of all matter (including all organisms) is to be inanimate.  Each of the trillions of biological components (5) that make up the human organism is itself a complex organism with a lifespan that is typically measured in days. Maintenance processes do not, and cannot, prevent those biological components from sustaining damage and dying. Complex metazoans are possible not because components are long-lived, but rather because, over the eons, metazoans have developed sophisticated maintenance processes that replace the components that die, thus allowing for the survival of the organism, notwithstanding the inexorable dying off of its components.

Maintaining a complex organism is an immensely complex and difficult task. Biological components are very different from machine parts. It’s estimated that a typical human loses over 50 billion cells per day, regardless of any wear and tear or extrinsic causes of damage. A damaged cell cannot simply replicate itself through mitosis, because that would create two defective cells. A damaged cell becomes senescent (i.e., it is unable to reproduce through mitosis). The senescent cell transmits signals that it is damaged. If the maintenance system is functioning properly, the senescent cell is destroyed (aptosis) and removed, and the maintenance system simultaneously replaces it with a healthy new cell. Identifying, removing and replacing over 50 billion highly specialized components per day is not a “doddle.”
Moreover, no biological process can be perfect. Even when the lower level maintenance processes are functioning in an optimal manner, some defective components are not removed and replaced, or they are replaced by components that are themselves defective. Damage or a flaw in any component at any level of biological organization can affect higher levels. A flaw at the molecular level can impact an organelle (e.g., mitochondria) in a cell that then prevents the cell from functioning properly; improperly functioning cells can affect tissues, organs, organ systems, and ultimately the entire organism. Unless each of the many maintenance processes that operate at various levels of biological organization is operating with optimal efficiency, intrinsic damage inevitably accumulates.
All life at all levels of biological organization fights a constant struggle against a universe that is trying to return it to its natural, inanimate state. Creating a complex organism is nothing like constructing a machine. A better metaphor would be a bird taking flight. Intrinsic damage can be likened to gravity – an inexorable force that will ultimately prevail. Sooner or later, all birds must succumb to gravity and land. And sooner or later, all components of all organisms, and ultimately all organisms, succumb to the universe and die, returning to their default state.
One may question why evolution never came up with a way to make our cells/other components indestructible. That would certainly simplify the problem. But that’s not the way evolution works. Unlike a blueprint created by an architect on a clean sheet of paper, genetic blueprints are the result of evolution picking and choosing among millions of random mutations, all of which are add-ons. It’s generally accepted that all animal life on earth is descended from a single eukaryotic cell. The eukaryotic cell that is the foundation of all multicellular animal life on the planet was itself quite mortal. The cells that are the basic components of all animals that are descended from the original eukaryotic cell are fated to share that fatal characteristic.

Overview of the Human Maintenance System

Prior to the acceptance of the Germ Theory of Disease in the late 19th century, science did not acknowledge the existence of the human immune system. It’s long past time for the scientific establishment to acknowledge the significance of the human maintenance system. The maintenance system is not a biological system in the anatomical sense of being a specific group of organs that can be identified by dissecting a cadaver. The maintenance system is akin to the immune system – a number of different biological structures and processes that perform a particular set of functions.
The healing process is the most conspicuous of the many processes performed by the maintenance system. When an organism is damaged by external trauma, the maintenance system responds by activating the healing process. That response is triggered by cells in the damaged tissues transmitting molecular signals that damage has occurred that could pose a near term threat to the survival of the organism itself. Because of the nature of the threat, the healing process responds immediately.
A less obvious feature of the maintenance system is its routine maintenance function. As noted previously, each day the human organism replaces over 50 billion cells that have suffered intrinsic damage. The maintenance system does not prevent intrinsic damage from occurring. Instead, when functioning effectively, maintenance processes keep the entire organism functioning at an optimal level by removing and replacing defective components. The healing process and these routine maintenance processes utilize substantially the same biological structures and processes. The difference is that the processes are occurring in response to different stimuli, thus resulting in different chemical signals. Among other things, those signals dictate how quickly the maintenance system responds, what resources are made available and where they are directed.

Specific Maintenance Processes

Although the critical significance of the human maintenance system may seem like a novel concept, scientists have long been aware of, and extensively studied, a number of different maintenance processes that function at multiple levels of biological organization. All of these processes involve the identification, removal and replacement of damaged components.

For purposes of illustration, this essay will briefly mention two maintenance processes that function at opposite ends of the organizational spectrum – mitochondrial turnover (sub-cellular level) and bone remodeling (tissue/organ level).

Mitochondrial Turnover.    Mitochondria are organelles within cells that are responsible for the generation of the energy necessary for cell survival through aerobic metabolism. Like all biological components, mitochondria have short lifespans, typically estimated to be about two or three weeks, even in the absence of any extrinsic sources of damage. (6)  Damaged mitochondria are replaced through a maintenance process known as “mitochondrial turnover.” Mitochondrial turnover involves the selective identification, isolation and destruction of damaged mitochondria (through fission and mitophagy), accompanied by the concurrent reproduction of healthy new mitochondria (mitochondrial biogenesis).(7)

Mitochondria should not be considered individual structures but rather as a reticular network. (8)  The organization of mitochondria into reticulum can be likened to cells of a similar type organizing into tissues, such as bone tissue. The mitochondrial network is dynamic in nature, with mitochondria joining and separating from the network in processes termed fusion and fission.

The mitochondrial content within the mitochondrial reticulum of a cell at any one time is a balance between mitophagy (degradation) and mitochondrial biogenesis (growth). The critical issue for mitochondrial health is not avoiding mitochondrial damage, but ensuring that there is adequate mitochondrial turnover. Turnover is the combination of selective elimination of damaged mitochondria (through fission and mitophagy), and reproduction of healthy new mitochondria (mitochondrial biogenesis).

Mitochondrial fission is the splitting of one mitochondrion into two. It differs from biogenesis in that fission is a process for separating out the damaged portion of a mitochondrion from the healthy portion. The damaged part of the mitochondrion is then selectively eliminated through the mitophagy process. Studies have shown that the mitophagy process selectively isolates and eliminates dysfunctional mitochondria.(9)

So long as the mitochondrial turnover process is working effectively, damaged mitochondria are removed and replaced, and damage does not accumulate. However each of the maintenance processes utilized by the maintenance system was designed to function optimally in a particular environment – the evolutionary environment. A significant deviation from the human evolutionary environment can disrupt the effective functioning of any such process.

Bone Remodeling.   No maintenance process works perfectly, and all biological components are constantly undergoing intrinsic damage and dying.(10)  Damage or a flaw in any component at any level of biological organization can affect higher levels. To prevent accumulating damage from having an adverse impact on the entire organism, natural selection endowed humans with backup maintenance processes that operate at each of the higher levels of biological organization.

Bone remodeling is an example of one maintenance process that operates at a higher level of biological organization – the tissue level.(11) Like substantially all cells in the human body, bone cells have limited longevity. Although maintenance processes do remove and replace damaged and dead bone cells, there is inevitably a buildup of accumulated damage in bone tissue. Bone remodeling involves the removal of damaged bone tissue (resorption), accompanied by the formation of new bone tissue to replace the old tissue. Bone remodeling is an active, ongoing building and maintenance process that begins at the embryonic stage and continues throughout one’s lifetime. (12)  In other words, the same bone remodeling process that is involved in the growth and development of the skeletal system in our youth remains available to remove and replace damaged bone tissue throughout our adult years.

Identifying Damaged Components.   Per the New Paradigm, the roll of the human maintenance system is to identify, remove and replace damaged and dead components.  Mitochondrial turnover and bone remodeling are two examples of maintenance processes that remove and replace damaged components.

The maintenance system removes and replaces over 50 billion cells damaged and dead cells per day.  How does the system identify which cells must be removed and replaced? 

A damaged cell cannot replicate through mitosis, because that would result in two identical cells that would also be damaged.  Such non-replicating cells become senescent cells, or “SCs.”  Although they can no longer self-replicate, SCs stay metabolically active.  SCs excrete a glut of molecules, including cytokines, chemokines and proteases.  It’s believed that these chemicals constitute both a distress signal and information regarding the type of cell involved. 

Under the current aging paradigm, the distress signals emitted by SCs are viewed as a possible cause of aging.  Per the inflammaging hypothesis (13),  in the presumed absence of a maintenance system, the job of eliminating SCs is left to the immune system.   With increasing chronological age, the immune system gradually loses the ability to eliminate SCs.  The SCs that are not removed continue to excrete signaling molecules which has an adverse effect on nearby cells, inciting local inflammation (inflammaging).  And that inflammaging is the reason why aging is inevitable.

The Institute has a very different point of view.  The New Paradigm posits that the chemicals emitted by the SCs are the signaling mechanism whereby the maintenance system identifies which cells need to be removed and replaced.  It is true that with increasing chronological age, the number of SCs in the typical human does increase.   That increase in the number of SCs is a manifestation of the accumulation of intrinsic damage that the New Paradigm labels FDS.   The intrinsic damage accumulates because an environmental factor interferes with the pertinent maintenance processes.  

Disorders Illustrate The Power of the HMS

The New Paradigm posits not only that intrinsic damage is an inexorable force, but also that it is much more powerful than generally believed. Perhaps the best evidence in support of this proposition comes from the symptoms of degenerative disorders resulting from an acute disruption of a particular maintenance process. Nutritional deficiency diseases provide a good illustration. Nutritional deficiency diseases result from a diet that lacks a nutrient that is essential for the proper functioning of one or more maintenance processes. For example, a human who suffers from acute vitamin C deficiency will develop the symptoms of scurvy.

Vitamin C is necessary in order for the proper functioning of a number of different maintenance processes. Among other things, vitamin C is necessary for certain enzymatic actions that need to occur in order for the body to create collagen, a substance that holds tissues together, and thus facilitates certain maintenance processes.  The absence of vitamin C does not itself inflict any damage. However, as a result of maintenance processes that utilize collagen being disrupted, intrinsic damage accumulates rapidly. The accumulated damage manifests itself as the symptoms of scurvy. The symptoms of scurvy can be quite devastating and even fatal. In fact, in the 18th century, the problem was so common that ship owners and governments assumed a 50% death rate from scurvy for their sailors on any major voyage.

Another example would be muscle disuse atrophy. At one time it was a common medical practice to confine a broken limb in a hard cast for up to six weeks. Upon removing the cast, the broken bone would be fine, but the muscle that was also confined by the cast would have undergone horrific deterioration. That deterioration is the result of the absence of muscular activity interfering with the effective functioning of a maintenance process (most likely, mitochondrial turnover).

The conventional model assumes that a maintenance system would not have a great deal of work to do. In fact, the human organism, like all organisms, is constantly under attack by the inexorable and powerful force the New Paradigm labels intrinsic damage. From that perspective, it is remarkable that the human maintenance system is as effective as it is.

Limitations of the Human Maintenance System

Humans do undergo certain physiological changes with advancing chronological age that are natural/genetically mandated. Those non-functional changes occur because the human maintenance system is not designed to prevent or reverse all age-associated physiological changes. Natural selection makes cost/benefit choices relating to the optimal way to allocate finite resources.

For example, once a human loses an adult tooth, the maintenance system will not generate a replacement. The evolutionary benefit to a human (as opposed to a shark, for example) conferred by a third set of teeth does not justify the additional energy/resources that would have to be devoted to that process. Hair follicles appear to be another example. Once a human’s hair is lost or turns grey, there appears to be no maintenance process that will reverse that result. For humans, losing hair or having it turn grey does not have a significant detrimental effect on survival or reproduction. Because these changes do not result from environmental interference with the normal functioning of the maintenance system, they are natural and not symptoms of the FDS disorder.
Also, it may be true that, like other mammals, there is a genetically mandated chronological limitation on the effectiveness of the human maintenance system. Thus diminished physiological performance that occurs much later in the life of a human may be an aspect of a natural aging process. The New Paradigm posits only that the functional declines (as opposed to the cosmetic and other physiological changes described in the prior paragraph) that occur early in the life of a typical human (say, prior to age 70) are symptoms of FDS. Since FDS is a degenerative disorder that results from environmental factors preventing the human maintenance system from performing in an optimal manner, these functional declines should be both preventable and reversable.

Conclusion

Substantially all physiological disorders are caused by an accumulation of damage interfering with the effective functioning of an organ or biological system. Frequently, as in the case of external trauma or infectious disease, the source of the damage is apparent. In those cases, damage “accumulates” because an external agent inflicts so much damage so quickly that, for a period of time, the countervailing process — the healing process or immune system, as the case may be — is overwhelmed.
The New Paradigm addresses situations where the link between the environmental agent and the accumulation of damage is not apparent. It’s not apparent why a lack of sunlight would cause damage to accumulate in our skeletal system. It’s not apparent why a diet that does not include vitamin C would cause the accumulation of damage that characterizes scurvy. The New Paradigm posits that these deficiency orders are a subset of degenerative disorders. Degenerative disorders are characterized by the progressive deterioration of the function and structure of an organ or system caused by an environmental factor disrupting one or more maintenance processes. Since intrinsic damage is an inexorable force, any such disruption will result in the accumulation of that damage.
  1. Williams, GC, Pleiotropy, Natural selection, and the evolution of senescence, Evolution (1957).
  2. De Grey, ADNJ, Life span extension research and public debate: societal considerations, Studies in Ethics Law and Technology (2007).
  3. See, e.g., Gladyshev VN, Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes, Aging Cell, (2016).
  4. Hayflick L, Entropy explains aging, genetic determinism explains longevity, and undefined terminology explains misunderstanding both. PLoS Genetics (2007).
  5. The New Paradigm uses the term “component” rather than cell, because cells are themselves made up of a multitude of components. Cells that would ordinarily have long lifespans can have their lives significantly shortened by the accumulation of damage to their components.
  6. Gottlieb RA, Gustaffson AB, Mitochondrial turnover in the heart. Biochim Biophys Acta (2011).
  7. Diaz f, Moraes CT, Mitochondrial biogenesis and turnover, Cell Calcium (2008).
  8. Ogata T, and Yamasaki Y, Ultra-high-resolution scanning electron microscopy of mitochondria and sarcoplasmic reticulum arrangement in human red, white, and intermediate muscle fibers, The Anatomical Record (1997).
  9. Frank M, et al., Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner, Biochimica et Biophysica Acta (BBA) – Molecular Cell Research (2012).
  10. Gladyshev VN, Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes, Aging Cell, (2016).
  11. Hadjidakis DJ, Androulakis II, Bone remodeling, Ann. N. Y. Acad. Sci. (2006).
  12. Id.
  13. See, generally, Franceschi, C, et al, Inflammaging: a new immune-metabolic viewpoint for age-related diseases, Nature Reviews Endocrinology (2018).

The next essay in this Section is “Scientific Revolution.”

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