Welcome to the blog of thelongevityproject.online, dedicated to graduate and postgraduate topics related to the physiology of aging I have written over the years, revised for ease of reading. My content is tailored for individuals 55 and over, providing unique insights on how proper lifestyle choices can mitigate the aging process. I encourage you to leave comments, contact me, and above all, become more educated on this vital topic.

                                                               I.  Biomarkers Related to the Aging Process

As an individual ages, key biomarkers can be observed that contribute to the degradation and eventual demise of the organism. This degradation or dysfunction starts at an earlier age than overt symptoms are witnessed.  What biomarkers start to degrade first depends on the lifestyle and genetics of the individual.  Nevertheless, a vicious cycle generally will begin, with the various biomarkers and their dysfunction feeding off each other, hastening the organism’s decline.  In the following research, I have chosen three biomarkers that are intimately connected, and in the real world, are surely most common.

                                                                                          Sarcopenia

The word “sarcopenia” is derived from two Greek words: the prefix “sark” translates to meat; the suffix “penia” translates to loss. (Bellanti, 2021).   As an individual ages, less hormone secretion is occurring, such as decreased testosterone, growth hormone (GH), insulin-like growth factor (IGF-1), and estrogen. If a practice of strength training is not ongoing as one ages to mitigate this loss by stimulating protein synthesis, the potential for falls and injuries are very common.  In fact, by the time individuals are over the age of 80, up to 50% of those individuals suffer from sarcopenia (Bellanti, 2021). 

Essentially, 2 major things are happening during the process of sarcopenia: there is a loss in muscle quality first, followed by a loss in muscle quantity. 

1. In a loss in muscle quality, a loss in strength can be noticed due to key structural changes, such as a decrease in the number of nerve cells that signal muscles to move (a key factor), defective anabolic signaling of GH, a general decrease in the macronutrient (CHO, fat, and protein) uptake, and a replacement of muscle tissue with fat and fibrous tissue.
2. Then later, in loss of muscle quantity, there is a decrease in both the number and size of muscle fibers.

A byproduct of one’s strength is power, and that power loss or velocity when doing repetitive tasks quickly is lost first to a greater degree than strength.  Power needs an explosive anaerobic system for increased velocity (type II muscle fibers); unfortunately, there is a decrease in the number of working nerve cells that trigger that power, even in the early stages of sarcopenia.

But engaging in sensible practice of strength training regularly, focusing on movements that challenge mobility and functional strength that simulate to some degree activities of daily living (ADL), one can preserve strength, power and muscle mass.  At least twice weekly is the current recommendation, with a 48-hour recuperation between those workouts (CDC, 2023)

                                                                             Mitochondrial Dysfunction

So, strength and power are adversely affected, but what about aerobic endurance?  Unfortunately, the aerobic system (types I and IIa muscle fibers) is adversely affected as well due to dysfunctional mitochondria caused by the aging process.  This ultimately also leads to sarcopenia.  In the healthy human, there is a delicate balance between mitochondrial biogenesis that creates new mitochondria, and mitophagy, the selective destruction of old or damaged mitochondria.  However, physical inactivity in the aging individual causes greater mitochondrial mitophagy due to oxidative stress, thus upsetting the delicate homeostatic balance.

Yet even in the elderly, mitochondrial biogenesis can occur via the practice of regular aerobic activity, which activates key signaling pathways (A master regulator of mitochondrial biogenesis is called peroxisome proliferator-activated receptor gamma coactivator 1 alpha). (Bellanti, 2021).   This begins a cascade of reactions leading to the production of proteins needed to synthesize new mitochondria.  Aerobic activity that is at a conversational pace, but the individual is breaking a sweat (zone 2) seems to be the best intensity for mitochondrial biogenesis. (Marshall, 2024).  The current recommendation is getting at least 150 minutes of cardiovascular exercise per week (CDC, 2023).

                                                                              Diastolic Dysfunction

Through the natural process of aging, exacerbated primarily by long standing hypertension, as well as other co-morbidities, the Left Ventricle (LV) of the heart (the chamber that is responsible for delivering blood into systemic circulation) becomes stiff and less compliant.  Essentially, concentric remodeling (scar tissue) occurs in the myocardium, caused by a rise in collagen within the extracellular matrix (Aurigemma, 2006).  As a result, the preload, or amount of blood in the LV chamber prior to LV contraction or systole, is decreased.  As a result of less blood leaving heart into systemic circulation with each heart beat, there is a decreased stroke volume, which translates into a decreased cardiac output (SV x HR/min = CO).  A lower CO translates into a lower VO2max, or how much oxygen one’s working skeletal muscles can extract.  This is known as diastolic dysfunction (DD), and it adversely affects an individual’s VO2max potential.

                                                                How can aerobic exercise mitigate DD?

Regular aerobic activity (not strength training) can reduce the stiffening of the heart muscle and thus improve the filling of the heart during diastole.  In fact, aerobic training for three to four months can significantly improve VO2max, decrease symptoms of shortness of breath with exertion, and improve quality of life measures (Fogoros, 2024).

                                                          What looks good on paper versus the real world

On paper, regular practice of strength training and aerobic activity as one ages can potentially postpone one’s demise for a decade or more.  In reality, not many individuals over the age of 65 are even close to practicing the minimum amount recommended to gain any benefit (CDC, 2023).  In fact, only 8.2% of older adults met the criteria for both aerobic and strength training activity (Kruger, 2007).  More recently (Pahor, 2014), this trend continues.  In the LIFE Study randomized clinical trial, after completing the structured exercise program for sedentary individuals, there was a one year follow up.  The physical activity group arm at this follow up had regressed to where the control group arm was regarding regular exercise, and the other arm of the study, the health education group, had at this point caught up to the physical activity group.

                                                                          How can retention be improved

What is the defining difference between people who continually exercise at a high level, despite orthopedic or other insults to their body, compared with more sedentary individuals?  The short answer is intrinsic motivation.  Individuals who exercise day after day, one decade after another are generally motivated by the enjoyment of running, biking, swimming, walking, playing a sport.  They may find personal growth through the process, as they feel stronger, healthier, more flexible, at ease.  They may find enjoyment in setting personal goals to attain.  They may find a sense of purpose or well-being from their chosen physical activity.  In contrast, with extrinsic motivation, individuals may want to improve solely physical appearance.  They may exercise for some reward, whether money, a vacation, a trophy. 

How can an individual become more intrinsically motivated?  I honestly do not have an answer.  As a strength and conditioning specialist, I can only guide and educate, and from that, motivate them in a way that is more sustainable.  Over the hundreds, perhaps thousands of individuals I have trained throughout my life, I have only worked with a small handful of individuals that were intrinsically motivated.  Those individuals will always exercise, whether I am in the picture or not, whether they are injured or recovering from injury or not.  I believe they appreciate my advice, guidance, creativity and intuition when working with them, but they could continue without me. 

One key element of their workout week that looks different, day in and day out from extrinsically motivated people, is their consistent desire to do other forms of physical activity on the days that I do not see them, for a more comprehensive exercise program.  After all, what I guide them through is but a drop in the bucket, and they realize that. 

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                                                                              II.  Environmental Enrichment

According to Francisco Mora (Mora, 2007), environmental enrichment can help increase many factors in the brain of elderly organisms that are necessary to keep it youthful.  One of the key factors that is stimulated through environmental enrichment and aerobic exercise is Brain Derived Neurotrophic Factor (BDNF), which enhances brain’s neuroplasticity by promoting synaptic plasticity, neurogenesis, and the actual survival of neurons.  BDNF is like miracle-grow for the brain, according to Charles Duhigg (Duhigg, 2012).  These structural restorations are crucial for learning, memory and mood (Marosi, 2013).

Neuroplasticity or neural plasticity is the brain’s ability to reorganize and restructure itself on a cellular level (Perry, 2021) as we adapt to changes through new experiences, new environmental exposure, and even brain damage.  Confronting a new environmental challenge requires neural networks to alter themselves and generate new connections.  Use it or lose it, as the saying goes.

There are many examples of cognitive enhancement that have been shown to improve neuroplasticity through various studies.  For instance, the MRI comparison in individuals learning to juggle versus the control group showed an increase in size in key areas associated with the visual processing of movement (increased size in bilateral mid-temporal grey matter; left posterior intra-parietal sulcus).  Similarly with London Taxi drivers versus the control group, the drivers showed greater growth and volume in the posterior hippocampus, important for spatial memory (Sage, 2014). 

Further, Erickson and colleagues found that training which emphasized intellectual challenges like semantic elaboration during a memory encoding task led to improved performance in older subjects, functionally activating the pre-frontal cortex (Sage, 2014).  This growth and development in the brain is due in large part to this reorganization and restructuring due to neuroplasticity.

But what about something more modern?  Can present-day technology such as video games act as an equivalent function that would provide environmental enrichment, and thus stimulate neuroplasticity and improve hippocampal function in individuals naïve to gaming?  At the University of California, Irvine, 39 self-described video gamers and 29 self-described non-video gamers were gathered for participation in a pilot study (Clemenson, 2015).  The control group played no games; The active control group played a 2-D game (Angry Birds); and the experimental group played a 3-D game (Super Mario). 

At the end of the study, the once naïve 3-D gamers had an increase in hippocampal stimulation, thus an enhancement in hippocampus-associated behavior due to playing a complex game requiring greater spatial aptitude than in 2-d games - or in any real-world environment because of obvious safety concerns.

Finally, can an old technology that has been around for centuries provide a similar amount of neuroplasticity stimulation? Yes.  Even in older adults, learning to play the piano has been shown to improve neuroplasticity.  Engaging in the challenge of sight reading a new piece, and refining skills to perfect that piece, promotes the growth of new neural connections (Xinyue, 2023).  Further, piano playing has been linked to cognitive preservation, including improved memory and executive function in older adults.  In fact, the structured nature of piano playing, along with its rhythmic and melodic attributes can facilitate motor recovery in individuals with a variety of neurological disorders, such as Parkinson’s disease and stroke.  And, as a side effect, you learn lots of cool tunes and are a hit at holiday gatherings.

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                                                     III.    Salt Sensitive Hypertension:  A different Treatment Paradigm

In salt sensitive humans, Signal Transducer and Activator of Transcription 3 (STAT3) is the most critical transcription factor for upregulating the angiotensinogen (AGT) gene, which leads to elevated blood pressure. 

There are several key upstream pathways that eventually converge to activate STAT3 in response to a high salt intake by ultimately activating the JAK-STAT pathway; then, downstream to STAT3, SMAD3 (Saleem, 2025) is activated (Sma from the nematode Caenorhabditis elegans, and Mad from the fruit fly Drosophila).

                                                                                       First, an overview:

In an individual who is not salt-sensitive, a high-salt intake normally suppresses the renin-angiotensin-aldosterone-system (RAAS) activity, leading to reduced renin and angiotensin II, and lower aldosterone levels.  This leads to a negative feedback loop where the body’s response to salt intake is to suppress the hormones that raise blood pressure.

In an individual with salt-sensitive hypertension, Ang II can continue to activate the RAAS through a positive feedback loop involving the intrarenal formation of angiotensinogen, often driven by pro-inflammatory cytokines like IL-6.  This leads to the activation of the JAK-STAT pathway, which further enhances Ang II production and signaling, independent of aldosterone levels.

Myeloid Antigen-Presenting Cells: they are cellular bridges between the innate and the adaptative immune systems because they contact a pathogen at the site of infection and communicate this encounter to T lymphocytes in the lymph node (Miao, 2022).

                                                                                    STAT3 and beyond:

• A high salt intake in salt-sensitive individuals leads to salt-sensitive hypertension by the release of renin from the juxtaglomerular cells (JG) in the kidney, which initiates RAAS inappropriately.
• Angiotensin II, a key hormone in the RAAS, directly increases inflammation by raising levels of pro-inflammatory cytokines, most notably interleukin-6 (IL-6) from activated myeloid cells, including myeloid antigen presenting cells (APCs), in turn, this upregulates the JAK-STAT pathway, through the Janus Kinases (JAKs), particularly JAK2 protein. Activated JAK2 phosphorylates STAT3 monomers.  This all occurs in the cell cytoplasm.
• Downstream and enhanced by the JAK-STAT pathway, SMAD3, a member of the Transforming Growth Factor (TGF) signaling pathway, is activated
• Once activated, the SMAD3 complex is translocated to the cell nucleus, where it can then bind to the angiotensinogen (AGT) promoter to initiate transcription.
• Further downstream, activated SMAD3 results in increased production of pro-inflammatory molecules such as IL-6 in the kidneys, activating T-cells and raising blood pressure, thus contributing to hypertension and damage, locally in the kidneys, and systemically (Saleem, 2025).

                                                  Preventing the Damage by using Myeloid-Specific JAK2 inhibitors

• Use inhibitor therapy specific to myeloid cells, thus target the root cause of salt-induced inflammation in those with salt-sensitive hypertension.
• The inhibitor blocks the activity of JAK2, which then halts the entire downstream cascade.
• This prevents the activation of STAT3 and SMAD3, thus mitigating the production of pro-inflammatory molecules.
• The overall effect in salt sensitive individuals dampens the inflammatory response in endothelium and lowers the blood pressure (Saleem, 2025).

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                                                                                         IV.  Young Blood

When a variety of species voluntarily exercise aerobically, certain enzymes are released that can reverse the brain’s aging process, specifically by reestablishing neurogenesis in the brain’s hippocampus.  For instance, plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI degrading enzyme derived from the liver, are released during aerobic activity that do just that.  If this enzyme could somehow be transplanted into sedentary mice from aerobically fit and active mice, it could, in theory, improve cognitive function in sedentary mice (Horowitz, 2020).  If effective, could this then be duplicated in humans with consistently positive results on cognition?  Would this help with diseases like Alzheimer’s?  If results were encouraging, how often would this installment need to be done?  Would there be ethical concerns if there were dramatic improvements at first, only to lead to the eventual regression and demise of the individual?

Preclinically with animal models, when Gpld1 and other important factors released during exercise such as brain derived neurotrophic factor (BDNF) were transferred from young mice to elderly mice, either by heterochronic parabiosis (where the circulatory systems of young and old are joined), or administration of young plasma to elder mice, improvements in cognition and increases in neurogenesis (confirmed by expression of the key markers BrdU and NeuN showing key neuronal growth in dentate gyrus of hippocampus) in the aged hippocampus were observed (Horowitz, 2020).  Parabiosis has been utilized in animal studies for decades.  Plasma injections are a more recent delivery system, which is simpler in its delivery system.

How does this translate to humans?  It has been shown through numerous studies that consistent aerobic activity throughout life mitigates cognitive decline and improves cognition in populations at risk for Alzheimer’s disease (Dhahbi, 2025).  But for elderly individuals that cannot reap the benefits of aerobic activity due to a variety of orthopedic and metabolic reasons, can the transfer of those key enzymes and factors be transferred over as was done in the preclinical setting?  As of now the results are mixed.

Clinically, there is no evidence according to neuroscientist Tony Wyss-Coray of Stanford University in Palo Alto, California, who was principal scientist in the 2014 study in mice (Kaiser, 2016).  Plasma injections from young blood to old blood in humans, nor parabiosis seem to have that positive effect that it did with mice.  In Ambrosia’s clinical trial, 600 people over 35 receive 1.5 liters over 2 days of a plasma injection from a donor under 25.  Pre and post blood tests compare more than 100 biomarkers that vary with age.  The results are analyzed.  The cost is 8,000$. 

In contrast, most platelet rich plasma injections cost on average 1,000$ (Boston concierge orthopedics, 2025).  Further, in most trials there is a placebo arm.  In the Ambrosia trial, there is none.  Thus, profits are ahead of actual improvements. But based on Wyss-Coray’s research and hypothesis that young blood injected into old could have benefit, a study was done in individuals with mild to moderate Alzheimer’s disease.  The results were modest, showing its safe effect on humans, with mild improvements in memory (Goldman, 2018).  If the intricacies of this model of treatment eventually get perfected where results are remarkable, then regular supplemental injection or infusion would have to be ongoing; otherwise, the individual will regress back to the less vibrant self. 

This reminds me of the book called Flowers for Algernon (which was eventually made into a movie).  In the book, researchers have found, through invasive laboratory tests, a way to make mice much smarter than normal, and therefore more complex mazes would have to be designed to heighten the intellectual challenge in order to develop new neural pathways.  After successfully completing their first experiment on the first mouse called Algernon, it was decided to try the same procedure on Charly, a human with mental retardation, but with a strong desire to learn.   Thus, in theory, the final results could potentially be very stark in contrast to the start. 

Charly’s initial IQ was 68 before the surgery, rising to a peak of 185, several weeks post operation - after weeks of nurturing new neuronal growth with challenging intellectual stimulation.  The story, told through Charly’s personal progress reports, shows how in the beginning his sentence structures were very basic with many grammatical errors; this is contrasted with his journaling several weeks out, where the sentence structures are quite complex with physiological and biochemical data beyond the scope of most scientists.  This unfortunately is followed by first the regression of Algernon the mouse, and then Charly, who is quite aware of his fate at that point, and his struggle to develop new interventions that would reverse the regression.  Thus, ethical questions come into the story, as well as the complex, emotional toll, which could hit home in a real-world scenario.

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                                                                              V.   Stem Cell Regeneration

       Stem cells are crucial for longevity because they can regenerate and repair tissue throughout life, containing the all-important chromosomes that in turn contain genetic instructions for that cell.  Thus, they are the body’s internal repair system, continuously replacing damaged or lost cells to maintain the function of organs and tissues on a more macro level.   But stem cell function declines or deteriorates as we age, impacting their ability to self-renew and differentiate properly.  This decline and deterioration are linked to shortened telomeres, which are the protective caps on chromosomes that are lengthened by the enzyme telomerase.  This enzyme expression is expressed by stem cells to enable more divisions.  However, the stem cells become shorter with each division, eventually not being able to divide.  This process is called replicative senescence (Pizzul, 2023).

       There are many different types of stem cells in the body, depending on their function.  For instance, mesenchymal stem cells are vital for bone and muscle; neural stem cells are crucial for brain health; hematopoietic stem cells (HSC) on the other hand are crucial to producing blood and immune cells, which are constantly needed to maintain the body’s health.  HSCs divide an average of 56 times over a person’s lifetime, with roughly half of these divisions occurring within the first 24 years of life.  As individuals age, adult stem cells like HSCs divide less frequently, with an average of less than one division every two years (Life Sciences, 2025).

       According to Oh, et al (Oh, 2024), there are several key strategies that can be used in theory to address aged stem cells:  using senolytic compounds that can induce the removal of senescent cells from aged tissues (quercetin and disatinib), or senomorphics that reduce the expression of senescent-associated genes and inflammatory factors without actually killing the senescent cells; targeting molecular pathways that become perturbed during aging, such as those involved in DNA damage, repair, and reactive oxygen species (ROS) production, by developing interventions;  and utilizing caloric restriction in order to improve stem cell function, potentially enhancing stem cell proliferation and function.  I will explore a couple of these potential avenues that could prevent or at least mitigate the stem cell from going down that path towards senescence and the corresponding inflammation to tissues.

                                                                                    Reactive Oxygen Species

       There is a longstanding notion that an increase in ROS may drive stem cell dysfunction with age.  According to Denham Harman, “accumulated cellular damage and declining mitochondrial integrity in aged cells leads to elevated ROS production, which in turn drives a vicious cycle that further damages cellular macromolecules and disrupts mitochondrial oxidative phosphorylation, leading to eventual cellular decomposition.” (Harman, 1972).

       The pathway perturbed by ROS are the DNA damage response (DDR) pathway, leading to cell cycle arrest via the p53/p21  and p16/pRB pathways, and the MAPK pathway.  The cascade of events starts with damage to DNA caused by ROS, which activates the DNA damage response  (DDR) pathway; this pathway in turn activates cell cycle arrest through the p54/p21 and/or the p16/pRB pathways.  Further, the MAPK pathway is also required for the activation of senescence in response to ROS (Oh, 2014).

       Therapies such as N-Acetyl Cysteine (NAC) have been shown to reduce ROS levels and DNA damage.  In fact, it has been shown preclinically and clinically to exhibit antioxidant, anti-infective, and anti-inflammatory activity, and its use as a mucolytic is well established (Santus, 2024).  NAC was first introduced in 1965 for its role in breaking up mucus, thus helping in the treatment of acute bronchitis, chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis.  Oxidative stress and inflammation contribute to the development of these pathologies.  NAC’s mechanism in pulmonary conditions involves the inhibition of the activation of NF-kB and neurokinin A production, resulting in a reduction in interleukin-6 production, which is a cytokine present in the sputum and breath condensate of patients with COPD. 

       NAC’s shielding effect against ROS may be attributed to its function as a precursor to reduced glutathione (GSH).  NAC is a synthetic source of amino acid cysteine, which is a building block for GSH; thus, NAC helps replenish the body’s stores of glutathione.  GSH is important because it directly scavenges various ROS, such as hydrogen peroxide and superoxide anions, and is a crucial co-factor for antioxidant enzymes like glutathione peroxidases (GPx).  These enzymes convert toxic peroxides into non-toxic water and alcohols (Santus, 2024).

       Under normal conditions, ROS act as important signaling molecules for normal physiological activities.  The GSH/ROS balance ensures proper cell signaling.  Under severe stress for instance, where ROS production overwhelms the antioxidant capacity of GSH, oxidative stress can occur, which can damage cellular components such as DNA, proteins, lipids, and lead to cell apoptosis.  GSH’s chronic depletion is implicated in various diseases, including neurodegenerative disorders and cancer (Liu, 2022).

       However, before reaching for the NAC bottle, it should be known that using synthetic NAC can have negative effects, particularly at high concentrations, or with long-term use, as it may disrupt the essential balance of ROS that is required for proper stem cell differentiation and signaling.  For instance, studies have found that while moderate ROS scavenging can enhance certain stem cell functions, complete ROS scavenging using NAC can completely inhibit the differentiation of some stem cells, such as human embryonic stem cells into vascular embryonic progenitor cells.  Thus, a minimal, physiological level of ROS is necessary for normal stem cell development and differentiation (Zheng, 2024).

                                                                                Mitochondrial Dysfunction

       Although the free radical theory of aging points to elevated ROS as a principal cause of mitochondrial DNA (mtDNA) mutation according to Oh, et al, (Oh, 2014), there is a more efficacious and safe way to improve mitochondrial function and therefore stem cell health without the use of supplements such as NAC that have a small window for safety and efficacy.  According to Cerletti, et al (Cerletti, 2012), caloric restriction leads to a greater number of mitochondria in muscle stem cells.  Because stem cells adapt to lower calorie states by shifting their metabolism from glycolysis to oxidative phosphorylation, mitochondrial function and efficiency is improved.  CR also modulates key signaling pathways like mTOR1, and sirtuin activation.  For instance, CR dampens the activity of the mTOR1 pathway, which is a key nutrient sensor.  The regulation of mTOR1 pathway is crucial for maintaining stem cell quiescence and self-renewal and preventing their premature differentiation and exhaustion.  On the other hand, CR activates sirtuin enzymes such as SIRT1, which promotes mitochondrial biogenesis and function via activation of PGC-1a and FOXO, further linking mitochondrial health to stem cell function (Kadharusman, 2021)

       In conclusion, some organisms such as the lobster have telomerase active in most of their cells for life, allowing them to maintain telomere length in most cells and avoid the limitations of cell division that lead to aging.  Thus, they could have a potentially indefinite lifespan.  Unfortunately, the molting process they undergo, particularly in later years, seems to be their downfall, as it takes tremendous amounts of energy to undertake the molting process and then the regrowth of a new shell (Berthold, 2025).  But a greater span of telomerase activity in humans would potentially precipitate greater potential for cancer development.  Perhaps if we better understood why some ethnicities do not show a decline in telomere length with age compared with controls, we could better understand genetic factors and potentially change them through epigenetic means. There is a correlation between Ashkenazi Jewish centenarians and their telomere length and lipid profiles compared with controls.  In the same association analysis, it was shown that individuals with hypertension, metabolic syndrome, or diabetes had shorter telomere lengths compared with subjects without these disorders.  Correcting this genetic deficit may prove advantageous (Atzmon, 2009).

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