AGING DEFINED

Having an accurate definition of aging is critically important. If you can’t effectively define a problem, you have virtually no chance of sucessfully addressing it. The focus and rational of this entire site is defined by the definition of aging provided above.

Our definition focuses on a primary feedback loop that may or may not be the final product of a long cascade of biological signaling events. As new insights into the root cause of aging emerge, the definition above will be refined. Josh Mitteldorf has identified potential age-controlling processes that each have independent influences on cellular and systemic health. Josh’s blog, is one of the best sources of news and information on the emerging science of aging.

• An epigenetic clock alters gene expression over time in directions that give rise to self-destruction.

• A telomere clock, counting cell divisions on a flexible schedule, eventually produces cells with short telomeres that poison us.

• The thymus, a crucial training ground for our white blood cells, shrinks over a lifetime.

• A neuroendocrine clock in the hypothalamus

We addrerss age regression by transforming the currently available research from multiple lab groups, biopharmaceutical companies and individual researchers, into understandable and actionable interventions, easily implemented by anyone. To quote one prominent aging researcher; “What works, what’s real and what doesn’t.” To address aging, you first must appreciate the most recent discoveries researchers have provided, describing and defining what the biological process we call aging, actually consists of.  To that end we provide above, our own amalgamation of the current definition(s) of aging, guided by the most current published insights. Of course there are other definitions held by credible scientist in the anti-aging field.

There is a critical point in the definition provided above that can be easily missed. Read the bare bones definition again.    “Aging is controlled by age-determining signaling molecules regulating the Biological Age-Set-Point.” If signaling molecules (chronokines) are directing all of the cells of the body as to what their assigned age should be, then those signals can be intercepted, blocked and/or replaced with “younger,” biological age-set-point signals. This description is believed by many to be a primary or first order directive of the aging paradigm. That process is depicted in the schematic above.

In a 2005 Letter to Nature, the Conboy’s research lab demonstrated this principle in mice. Our experiments suggest that there are systemic factors that can modulate the molecular signalling pathways critical to the activation of tissue-specific progenitor cells, and that the systemic environment of a young animal is one that promotes successful regeneration, whereas that of an older animal either fails to promote or actively inhibits successful tissue regeneration. It will be of great interest to identify the factors that have such a critical influence on tissue-specific progenitor cells. Our studies also demonstrate that the decline of tissue regenerative potential with age can be reversed through the modulation of systemic factors, suggesting that tissue specific stem and progenitor cells retain much of their intrinsic proliferative potential even when old, but that age-related changes in the systemic environment and niche in which progenitor cells reside preclude full activation of these cells for productive tissue regeneration. [12]

⫸ The blood delivers nutrients, oxygen, hormones, and growth factors to all organs and tissues. Moreover, it also transmits orders to the entire body and controls the immune system [52]. An age-related change in the profiles of bloodcirculation factors reflects the processes and mechanisms of aging. The medical implementation of these factors into the bloodstream allows conveying signals to the internal body systems that regulate and monitor aging [27]. ⫷[9]

These processes are staged, that is non-linear. [10]

⫸ Harold Katcher wrote in 2013: if a cell is placed in a “young environment” or an “old environment” that cell will assume the age phenotype appropriate to its environment. In agreement with the effects of the systemic environment on aging, aged stem cells were rejuvenated by young plasma in vitro, and young stem cells were “aged” by in vitro exposure to plasma from old animals [32]. ⫷ [11] Harold Katcher’s most recent advances in the field of age regression can be reviewed on this page.

This observation makes the regressive treatment directive simple and achievable. Block the increasing, negative signals advancing the age-set-point and augment the decreasing, positive signals regressing the age-set-point backwards. 

It should be pointed out at this point that we are not in any way ignoring the factors in control of this process. Increases in methylation “marks,” are directly associated with the advancement of aging. [13] Genetic control of the signaling milieu is not in conflict with the interventional goals or goal post described here. See: Epigenetic Reprogramming

There are effective age-regressive therapies that appear to contradict this definition. Gregory Fahy’s thymus regeneration protocol incorporating Human Growth Hormone (HGH), metformin, and DHEA to re-constitute the thymic microenvironment would be one example. But after further examination this also clearly falls within the definition provided above. The thymic involution/atrophy is the direct result of proteomic signaling. This decline in thymus function, in all probability, represents the first biological and clinical demarcation point where aging begins. That would put the starting gun of this deleterious pathway at around 15 years of age.

Currently multiple research groups are attempting to determine if any one, or any subset of the identified chronokines are deterministic for controlling the biological age set pont of an individual.  It now appears that a subset of these chronokines hold the possibility of being first order age-determents.

The viability of each approach can now be easily confirmed utilizing epigenetic clocks. [1,2] Clinical observations, normal blood cell and chemistry panels can also provide valuable feedback and validation on the effectiveness of your own current interventional strategy. [3,4]  These effective and highly correlated validating processes are confirming both that the definition of aging provided above is accurate, and that the targets identified within the articles and the articles referenced, are points where active interventions are addressable by a targeted armentarium of multiple modalities we collectively refer to as AIR. These Available Interventional Resources (AIR) include: Amino Acids, Hormones, Vitamins and Nutritional Supplements, Metals/Minerals, Pre and Probiotics, and Small Molecules/Drugs. That list would not be complete without the addition of diet, exercise, sleep and psychological support. The vast majority of the required targeted agents identified herein are readily available.

Changing the controlling directive of the plasma fraction proteins in the peripheral blood stream, signaling milieu, to a younger age-set-point is now a realistic and achievable goal.

Over the next few years expect an avalanche of new treatments targeting these pathways.  Many of them will initially seem to be disease specific targets because the FDA is still developing a clear pathway to develop drugs that are specifically designed and designated to regress aging.  At least for the short term, this requires developers to identify the most likely disease process that will be beneficially altered by these new modalities.  If these interventions are targeting a disease associated with aging, utilizing the chronokines identified within this site, it will be easily understood by you, that the mechanism is regressing the BASP to ameliorate that one specific and targeted disease indication.  It will also be understood that this new drug application will have broader anti-aging or BASP regressing capabilities. Until these drugs become readily available, AIR interventions are powerful and effective alternatives. 

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Aging is now emerging as a biologically segmented, incremental staged process that is harmonized, coordinated and synchronized at each step by intracellular and extracellular molecular signaling pathways, driving complex, multifaceted, positive/negative-feedback loops. [5]

All of these networks are entangled, even if they seem completely independent of each other. These networks control all physiological age-associated changes in all mammalian organisms. “These changes include proteomic, transcriptional and epigenetic modifications; changes in energy production within mitochondria; and alterations in the molecular biology or mechanistic interactions of cells, their nuclei, and their surrounding extracellular matrix. In addition, aging influences the ability of cells to sense changes in extracellular-matrix compliance (mechanosensation) and to transduce these changes into biochemical signals (mechanotransduction).”[6] It has now been definitively proven that the signaling pathways directing the aging pathways, (primary blood circulating factors), in all mammalian organisms can be redirected to regress the age state and amarillite the degenerative processes associated with aging, allowing for extension of both health and life spans.[7]

A principal controlling component of this network consist of signal molecules generated by intra and extra cellular factors transported to all cells by the plasma component of blood. This age defining system includes complex signal response loops, driven by multiple feedback signals and crosstalk between exogenous, molecular and genetic pathways. It is now possible to strategically amplify (up-regulate) or block (down-regulate) these signals redirecting the accretion aging paradigm.  This enables us to utilize the same molecular and genetic pathway targets to mimic the cellular signals normally directing and driving the aging process.  Biosimilar signaling agents can be introduced in the form of [a] small molecules or drugs, [b] biological agents, [c] nutritional foods and [d] supplements or nutraceuticals, [[8] to accomplish this goal.

Noise is also a contributing factor. Aging has multiple pathways that contribute to the network of signals controlling your BASP. The viability and health of cells diminishes during each cellular replication cycle. These cellular replications are necessary to replenish all tissues and organs in our bodies. During each replication cycle, genetic information can be lost through a variety of mechanisms. Degradation of the genetic code also degrades the cells viability impacting its health, functionality and biological age. This process can be referred to as Reproductive Noise Damage (RND). An insightful doctoral dissertation; “Reversal of aging via in vivo epigenetic reprogramming,” by Yuancheng Lu. provides an excellent and detailed description of this process.

The network of differentially expressed genes (DEGs) as well as the progressive silencing of genes, are also a driving confluence that both receives signals and direct protein and chronokine instructions. DNA can be directly methylated through the covalent linkage of a methyl group to the fifth position of the cytosine ring to generate 5-methylcytosine (5mC). This modification is mainly present in DNA regions rich in cytosine-phospho-guanine (CpG) dinucleotides. While there is extensive evidence that DNA methylation at promoter regions is associated with gene silencing, the decipherment of the function of gene body methylation is still ongoing [15].

The selective pressures influencing our understanding of aging in the perspective of this stochastic storm of crosstalk between exogenous and endogenous signals, molecular pathways and gene signaling has not been completely elucidated, but candidates, those with clearly evident influence on the aging process and thus the most obvious and efficacious targets of immediate intervention have been identified enabling a new level of control of our biological age.  

The information is available now to impact the aging process in a nominal way. As interventional information emerges from the ongoing research the ability to intervene in more dramatic way will become available in a time frame that will shock everyone.