Determinant Factors of Human Longevity

We live in an age of incredible scientific discovery, especially in the human biological sciences. Although new research into the field of anti-aging appears in scientific journals on a regular basis, we find ourselves on the cutting edge of a new understanding that may unlock the keys to life extension. In fact, the integration of this new research is the foundation of a new understanding we call: “Extended Longevity”.

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Aging is a universal feature of life, ranging from unicellular micro-organisms to humans. Longevity depends on the maintenance of cellular functionality, and on the organism’s ability to respond to stress.  Lifespan is also regulated by genes controlling the activity of metabolism, antioxidant systems, DNA repair, cellular senescence, and cell death. Their functions gradually decline due to random errors in DNA replication and damage to macromolecules, which leads to the accumulation of senescent cells and damaged tissue with age. Various signs of aging have also been linked to genomic instability and have indicated the role of DNA damage accumulation in the aging process and the development of age-related diseases, including heart disease, cancer, diabetes, Alzheimer's disease, and the auto-immune diseases.

Although aging is common among almost all multicellular organisms, there are exceptions. The existence of species with an observable extended time-dependent functional decline, termed ‘negligible senescence’, suggests that the aging process can be affected by both internal and external conditions, which may lead to a modification of the aging process.

 

Medical research traditionally treats the consequences of aging, not the underlying condition. In short, medicine today is geared toward managing outcomes – i.e. diseases that are the downstream results of aging.  Multiple molecular pathways operate collectively to regulate biological aging. Extended Longevity products target indications where disease pathogenesis has a clear relationship to the biology of aging.

Most scientists agree aging is currently inescapable, that it is characterized by the progressive loss of functioning of our bodies and that it is the principal cause of what we call the Diseases of Aging (Cardiovascular Disease, Cancer, Respiratory disease, Diabetes and Dementia) and that its path is inevitably towards death.

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There is a preprogrammed camp that believe that there are biological “clocks” ticking away in our cells, affecting gene expression and/or hormonal signaling, and/or that there are other gravitational forces that prevent us from outrunning death.  Others suggest that the accumulation of damage to different types of deoxyribonucleic acid (DNA), mitochondrial and nuclear, as well as the effects of free radicals or reactive oxygen species (ROS) and cellular senescence and failures in cell signaling, as being responsible for aging. Our opinion is that aging is multifactorial. In order to address these conditions of aging Extended Longevity has developed ten synergistic and mimetic formulations.

 

We now know that aging is related to genetic pathways and to biochemical reactions, some of which are conserved in evolution, and that aging is related to damage of a variety of sorts, caused by the simple fact that we exist and can’t escape our environment.  

Aging is primarily a degenerative process that is controlled by time-sequenced internal biological clocks, whose effects are felt as we age, across the human organism, and by systemic and cellular reactions to internal and external conditions.

The role of cellular and systemic mechanisms in aging-associated diseases can be defined as a state of progressive functional decline accompanied by an increase in mortality.

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Evidence shows the contribution of cellular senescence to age-related tissue dysfunction. Eliminating senescent cells has shown potential in resolving age-related disorders, which may increase lifespan. Because of a senescent associated secretory phenotype (SASP), senescent cells are capable of coordinating distinct non-cell systemic responses that disrupt tissue homeostasis. The links between cellular senescence, inflammation and stem cell exhaustion reflect the link between different determinant factors of human longevity and how multiple physiological factors coordinate the onset of age-related functional decline.

Inflammation is a defense response of our body to hazardous stimuli. The inflammatory response is the main cause of a vast continuum of age-related disorders. Chronic inflammation, caused by low-grade persistent inflammation, leads to tissue degeneration and is a contributor to various age-related pathologies and natural processes in aging tissue. One of the major changes that occur during aging is the dis-regulation of the immune response, leading to a chronic systemic inflammatory state. Among pro-inflammatory mediators, cytokines and chemokines are major targets in the development of chronic inflammation and the immunosenescence process.

Research has determined that a "resting" of the Pineal gland function by supplementation of melatonin, rejuvenates the Pineal.  The pineal gland regulates the cyclic production of the hormones of our body by producing melatonin, and as we age it produces less and less. Melatonin has been known to significantly reduce the oxidative stress burden of aging cells or cells exposed to toxins. As melatonin levels drop, we begin to exhibit signs of aging, because the pineal gland aging clock breaks down. When this happens, it signals other parts of the body that it is time to age.

It is scientifically well known that from the age of thirty our Thymus gland, which is responsible for producing immune resistant T-cells, begins to involute and by the age of 65, most of the Thymus has been replaced by adipose fat, with consequent loss of immune function.

Telomeres are the protective caps found at the ends of your chromosomes that protect our genetic information during cellular division. For our bodies to heal and function properly, cells must divide to produce new cells to replace old, worn-out cells. Telomeres allow our cells to divide without damaging or scrambling the cells’ genetic information. Telomeres are like the plastic tips on shoelaces, as they keep the chromosome ends from tangling and fraying. When we are born, our telomeres are at their longest. With every cell division throughout the course of our life, our telomeres lose a bit of their DNA. With age and accumulated exposures to various sources of oxidative stress throughout our lifetimes, telomeres gradually shorten, until the cell cannot replicate. This shortening process acts as an aging clock counting down the remaining life of the cell. At a certain point, chromosomes in the cell reach a critical length and can no longer be replicated. This can now be reversed. The longer the Telomere, the longer the cell life.

In other research, through experimentation with heterochronic parabiosis, a young and old animal are surgically connected to share a common blood circulation, it was discovered that there were age-related signaling molecules circulating in the blood that told all of the body's 100 trillion cells to age.  It was also discovered that this process can be reversed.

 

It is also now established that there are several important pathways related to aging, with notable ones being the nutrient sensing pathway, known as insulin/IGF-1, which is the most conserved pathway across multiple species, ranging from worms, to mice, to us. As an example, mutations that interfere with IGF-1, causing growth hormone to become dysregulated, are well known to influence longevity in some types of mice. The results of caloric restriction (CR) validate the following fact: longevity is increased through the regulation of nutrient-sensing pathways and genes, such as mechanistic target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK) , sirtuins and insulin-like growth factor 1 (IGF-1).

 

It is widely understood that many patients treated to date with one-process/one-drug approaches fail to respond adequately. We believe the primary reason for this failure is that current methods merely target the downstream effects of aging. The diseases are being managed rather than addressing the root causes of these disorders.

 

Aging is a continuation of a timed growth development program evolving into a phase of late-life self-annihilation. The body adapts to a variety of environmental stresses.  These stresses may affect the adaptive responses of specific cellular processes and create resistive strengthening leading to increased longevity.  The tendency of the organism to rebalance toward homeostasis is a biological response to both environmental and internal organic conditions that are determined by behavioral processes such as diet, stress, and activity, but can also be affected by certain drugs and/or herbal interventions.

​​A New Approach - Our research pursues an exciting and revolutionary alternative: targeting the pathology and underlying biology of aging itself. Therapies derived from this kind of effort have the potential to treat multiple diseases simultaneously. Research has determined that aging is largely controlled by ten (10) primary internal biological factors, now understood to be reversible. Here they are listed hierarchically, most important to least important:

 

  1. Pineal clock- (Pineal / Hypothalmic/ Pituitary/ Superchiasmatic Nucleolus (SCN)  axis) this is the master time clock and coordinates the body's circadian rhythm and the time-cycled release of melatonin and other critical hormones and neurotransmitters.

  2. Thymic involution- immune depletion, and T-cell diminution.

  3. Blood signaling and transcription factors- reverse distributed blood signaling of TGF-ß1 and Oxytocin (to all cells).

  4. Telomere length- Attrition of the protective chromosomal endcaps causing programmed Cellular senescence.

  5. Senolytics- (autophagy, mitophagy) Accumulation of senescent zombie-like cells that inflame and signal senescence to healthy cells. Centers on the removal of cellular waste associated with aging and disease.

  6. Inflammaging- Inflammatory response, altered intercellular communication and the production of inflammatory cytokine and chemokine molecules.

  7. Stem Cell Exhaustion- loss of source stem cells.

  8. Cellular Metabolic Efficiency (NAD, NMN, NR, Sirtuins, Resveratrol, ATP, ROS)- Energy production and mitochondrial dysfunction.

  9. Epigenetic clock (DNAm cytosine methylation)- Alterations to the epigenome that control which genes are turned on and off.

  10. Extra Cellular Matrix Stiffening - The decrease in elastin, in turn, increases collagen content and ECM stiffness. This causes age-related diseases such as hypertension, and atherosclerosis.

 

• Two factors are endocrinological: Pineal/ Hypothalamic /Pituitary/ SCN axis, and Thymus involution, which are internal aging-clock related.

• Two factors are DNA based: Telomere length and Epigenetic DNA methylation, which are internal aging-clock related.

• Two factors are cellular: Cellular Metabolic Efficiency and Senolytics, and are adapted systemic responses. 

• Four factors are Systemic: Blood signaling, Extra Cellular Matrix Stiffening, and Stem Cell Exhaustion, which are internal aging-clock related and Inflammaging, which is an adapted systemic response.