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. 

Ben Barrett

                                                                              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.

                                                     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).