The Road to Longevity: Leveraging Homeostasis to Slow Cellular Aging

The Road to Longevity: Leveraging Homeostasis to Slow Cellular Aging

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It is time for my birthday next month. As I inch another year closer to my fiftieth birthday, I contemplate the question that many of us ask: am I as healthy as I can be to live a long lifespan and healthspan?

To be clear, these words have distinct meanings: lifespan is the duration of one’s life; healthspan is the duration of one’s healthy years. For you to live a successful life, by these terms, would be living your whole life being able to stay healthy, active, and participate in hobbies and interests until one night, after you are 100 years old, you die in your sleep. To have a long healthspan means having only a short period of disease just before your life ends.

We can agree, that no one decides that they are going to live a long life, without living it right now, whatever the age. Although time is what is measured when we celebrate birthdays, the optimal functioning of our bloodstream and homeostatic balance is what gets us there.  How can we all seize the day and begin to live each day for longevity? 

 

 

The Origin of Life and the Hostile Environment

At least, in theory, the origins of life on this planet began around 3.7 billion years ago when a mixture of chemicals, a primordial soup, somehow blossomed into life. Molecules combined into larger groups, offering a degree of protection from exposure to, at that time, Earth’s hostile environment. The theory posits that lightening or other electrostatic charges may have become a catalyst for elements like carbon and nitrogen to become arranged into nucleotides, the building blocks to RNA. This was simulated in a famous experiment conducted by Stanley Miller and Harold Urey in 1953 (Scoville, 2020). In 2016, Carrell’s team had found a way to generate the nucleic acids adenosine and guanine from chemicals spontaneously.

 

As if driven by supernatural forces, life, under our genetic code, seems to propagate for the sake of living.  In humans, the fertilized egg, or zygote, seems to transcend stages of evolution from a single cell to the 26 trillion cells of a newborn. The code for the identity of this newborn, the eye color, the proteins produced by the body, is carried by every cell. Cells form into tissues; tissues form organs; organs become parts of systems that the body encases in the protective coat of the skin.

 

Our bodies transmit oxygen and other nutrients through the bloodstream to every cell in them by the heart.  This structure already begins to form only 18 days into the development of the embryo, becoming the first organ.  Something happens when cells aggregate into tissue: oxygen is no longer able to diffuse from the placenta into these cells.  Three days later, the heart begins to beat.  Circulation expands from this setpoint.  The process of growth becomes a chain reaction, bathed by nutrient-rich and oxygenated blood.  Vessels propagate, a process known as angiogenesis; nerves grow in a similar fashion, intimately situated with blood vessels. Around them and fed by them are the organs and tissue that are found in and shape our body.

 

Life seems to flow until it no longer does. An infant born today is expected to live as little as 50.6 years, if it is born in Chad, to up to 88 years in Japan, a difference of 38 years. We discussed some of the factors that shape life expectancy before but consider the simple concept that life takes a toll on the living. Whatever may be the driving forces of lifespan, including infections, trauma, and chronic illnesses, the body does not just succumb to any pressure that it faces.  It adapts until it no longer can. This process is known as homeostasis.  The vascular system is critical in this process.

 

Imagine a single-celled organism, like an amoeba, living in a pond. It measures 0.25 millimeters and can be seen only with a microscope. It has a layer of lipids and proteins that make up its outer membrane.  It is a primitive “skin,” or plasmalemma, that allows various ions, water, oxygen, and carbon dioxide to diffuse into and out of the cell.  Within the inside of the cell, or cytoplasm, is housed a nucleus, which contains all the genetic information of the cell. Also, in the cytoplasm are mitochondria, which provide energy for the cell’s activities.

Amoeba_proteus_x_100
Amoeba Proteus. Source Microwiki

 

Within this single-celled organism are the mechanisms to maintain it within a sometimes-hostile environment. This organism interacts with the environment by shaping its body into finger-like projections, known as pseudopod.   The cell “behaves” in different ways, in response to stimuli in the environment.  The cell either moves toward or away from a stimulus, such as contact, chemicals, heat, gravity, light, electric, and water currents (Shah, Richa). If the conditions become too unfavorable, it develops into a cyst until improved conditions return.

 

Life in multicellular organisms such as humans is vastly different. Human cells are more protected from direct exposure to the environment. They adjust better to changes, without the need to halt life and develop into a cyst. When the environment is too dry or contains too much salt, a single cell would otherwise die or lyse. Multicellular organisms adapt and develop within the environment. They contain specialized systems that are exposed to the environment and incorporate it into the system.  Depending on the stimulus, a more developed nervous system governed by the brain can problem-solve ways to reduce the harms of the environment or guide the body toward or away from it.

 

As with any cell, a multicellular organism requires nutrients to sustain each cell. This is accomplished through the network of the blood vessels that connects every cell with substances to nourish them, to provide oxygen, and to repair or protect cells. These coordinated processes ensure that the human body will survive for many years.  However, changes build-up that begins to impair the system and lead to disease development. These changes are orchestrated by the vascular system.

pexels-photo-4466054
Leaf Venations are a great visual for the purpose of the vascular system

 

If you measured the length of one human’s blood vessels end-to-end, it would measure approximately 60,000 miles.  The smallest of these blood vessels measure five micrometers, just large enough to allow a single blood cell through. The diffusion of oxygen can then occur to nearby cells. The heart conducts the flow of oxygen and nutrients, acquired from the lungs and intestines, respectively, toward every tissue of the body.  The veins return metabolic wastes and carbon dioxide back to the heart to repeat the process. The lungs and kidneys eliminate waste products in expired air and urine, respectively.

 

It is within this process that lies the secrets of longevity and the source of disease. The blood provides factors within it to enable vitality and healing to any damaged tissue. The bloodstream is a circuit with entry points. Unlike single-cell organisms, nutrients are not able to simply pass through our outer membrane into our bloodstream. Apart from certain chemicals, gasses, or pathogens that can pass directly through the first few millimeters of our skin and enter the bloodstream, the usual routes of entry into our bodies is through injection (skin entry), inspiration (air), and ingestion (food/drink). Through these routes, toxins can ultimately gain entry to our bodies and affect it.

 

 

circulatory system

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An Optimal Vascular System Provides Optimal Health

From the descriptions in the previous sections, I hope you can begin to see how important our vascular system, or cardiac fitness, is with the life of our tissues, and therefore, our longevity. Studies have found an association with cardiac fitness and decreased mortality risk; less fitness has been associated with higher mortality risk.  The greatest benefit was seen through high aerobic fitness (Mandsager, 2018).

 

When evaluating supercentenarians, those living past 100, reaching up to the age of 110, there was a relative lack of cardiovascular disease, with fewer than 15% with a history of vascular-related disease in one study (Schoenhofen, 2006). The majority of supercentenarians that are female (90%) compared with male.  A significant number of supercentenarians only required minimal assistance or were independent (41%).  Conditions such as heart disease, heart attack (6%), Parkinson’s disease (3%), diabetes (3%) were also relatively rare in this evaluation of 32 supercentenarians.  Autopsy studies (4 subjects) found relatively mild to moderate neuropathology in the supercentenarian brain, in the setting of mild cognitive impairment prior to their death. All these diseases are associated with changes in the vascular system.  When the vascular disease is absent or minimal, we can live a long life with a shorter duration of morbidity.

 

Precisely the mechanism behind the relative slowing of the aging process seen with longevity is beyond the scope of this article.  Suffice it to say that aging occurs as molecular signals gradually induce changes that impair cell structure and function. On our skin, we see wrinkles, changes in turgor and color, and the whitening of hair.  However, all tissues undergo these changes that lead to a decline in structure and function.  There is a decline in hormones, secreted by the sex glands, thyroid, pancreas, and other endocrine organs, as tissues atrophy and scar.  There is a decline in organ function, including the heart, liver, pancreas, lungs, kidneys, and brain.

 

When we age, every system ages. According to Gerontologist Denman Harman, aging is, “the progressive accumulation of changes with time that are associated with or responsible for the ever-increasing susceptibility to disease and death which accompanies advancing age.” Hayflick refers to age as “the common denominator that underlies all modern theories of biologic aging changes in molecular structure, and, hence, function.” (Harman D, 1981; Hayflick, 2007).  Henman espouses the free-radical theory of aging, which proposes that aging is the result of oxidative damage to cells and tissues (Wickens, 2001).

 

Although our chronological age is inevitable, we do have some effect on its accelerated changes on tissues, and therefore, our longevity. Through the air we breathe, the food and drink we consume, and the emotions we experience, we can either support health or trigger disease. Our environment, real or projected (our interpretive bias, stress level, and emotional reaction), can influence our vascular system.  Dangers, whether they are toxins, substances (sugar, processed foods, alcohol, tobacco, and drugs), pollution, or toxic stress, can activate a system known as the psycho-neuro-endocrine-immune system (PNEIS). This system is the manner in which our body regains homeostasis, healing inflammation. A cascade of damage-associated molecular proteins (DAMPs) participates in numerous responses that lead to the activation of the inflammatory system. This inflammation leads to functional decline in homeostatic mechanisms and disease, which results in a downward spiral of cellular decline. The endproduct is fibrosis (scarring) of the endothelium (the lining of the vessels) and other molecular changes, beginning in the cellular genetics and epigenetics. You might notice someone who is older by their wrinkles, but we age from our vascular system, inside-out.

 

Diabetes: A Model of Vascular Aging

The pathophysiology of diabetes mellitus provides a model to understand how conditions can contribute to vascular dysfunction and result in cellular changes. Diabetes is a disease associated with high levels of sugar in the blood following a decline in insulin production when beta-islet cells are depleted and resistance in insulin in the tissues from high adipose (fat) stores. Although glucose is fuel for our body’s tissues, when in excess, such as from the foods that are ingested, the higher levels of glucose can be toxic and lead to damage at the cellular level, including in the pancreas.  Insulin levels are required to maintain glucose in a range that is seen in a healthy state, around 60 to 90.

With increased ingestion of sugar in the diet, through simple sugars or ultra-processed carbohydrates, which lack the original fiber of vegetables, the glucose levels require insulin to mobilize it into the cells of the brain, muscle, and adipose tissues (increases uptake of triglycerides).  The adipose tissue stores increase and put demands on the body, both metabolically and structurally.

In diabetes, glucose levels cannot be kept in the “sweet spot” for the vascular system.  Consequently, high levels of glucose circulate around the entire body, form complexes with tissues (including the skin, vessels, nerves), and lead to direct inflammatory changes. Several mechanisms are likely involved in the damage, but there is a significant role in oxidative stress from high glucose concentrations, as described in the kidney disease of diabetes (Miranda-Diaz, 2018). Essentially, the high levels of glucose impair the mitochondria, the powerhouse of cellular metabolism, and leads to damage to its DNA.  Ultimately, the damage begins to show up in impaired proteins and further cell decline, which leads to the programmed cell death or apoptosis of the cell.  Little by little, high sugars in the vascular system induce inflammation, cellular damage, and death.

A person with poorly controlled diabetes has accelerated changes that are normally seen with aging. Cells become senescent at an advanced pace in diabetes, and leads to the similar associations with aging, including accelerated atherosclerosis, increased cancer risk, increased heart disease and stroke risk, chronic kidney disease, osteoporosis, and cognitive impairment. Essentially, a person with diabetes ages faster than those without the conditions. Just ask a surgeon to describe the difference in skin healing and infection rates seen in someone with diabetes compared to those without. Wound healing is impaired and infection rates are higher:  all because of the decline in the vascular system from diabetes.

 

 

Summary Points of Principals of Growth and Disease in Complex Systems

 

  1. Ease and dis-ease are associated with the state of the vascular system.

Our vascular system is intimately connected with our entire body.  Centenarians have an extremely low rate of vascular disease compared to their counterparts who died, even decades earlier. The vascular system is the conduit of the immune system and healing. Optimal health entails mental, endocrine, immune, and structural resilience.

Through our vascular system, the food we ingest and the air we breathe in is incorporated into the rest of our bodies.  Our brain interacts with the body through the vessels – in creating movement and affecting our system by interpreting the environment, and affecting stress or relaxation.  Hormones travel through the vascular network and conduct how the bodily functions metabolically or how it responds to stress. The hypothalamic-pituitary-adrenal axis coordinates responses for the autonomic nervous system – which leads to hormones that control our bodies and lead to inflammation.

 

  1. Every cell is “exposed” to the environment by our bloodstream, as it enters via the filter systems of the gastrointestinal (GI) tract and Lungs.

Our system interacts with the outside through our bloodstream. The air we breathe is directly exposed to our vessels in the alveoli and propels through our body in the form of oxygen. The pollutants in the air, including smoke, also may enter.  We eat food that is broken into components in our upper GI tract and absorbed into our bloodstreams (hepatic system) from the intestines. Pathogens are injected, ingested, or inspired; some are rarely able to penetrate the skin.

 

  1. Complex organisms have multiple mechanisms to buffer the system from a direct insult and maintain homeostasis. This process declines in the setting of disease.

Our bodies are capable of balancing forces to an extent to allow ongoing efficiency, even after a direct insult, such as alcohol, exercise, dessert, and stress.  This is the purpose of the immune system/inflammatory system. Disease is a gradual or sudden unraveling of the body’s ability to recover. Aging is, in part, a dis-ease associated with a buildup of proteins, more harmful substances, and changes, which lead to diminishing homeostatic control.  Chronic diseases, such as diabetes, hypertension, and heart disease, accelerate the changes that would otherwise come more slowly with aging. These chronic diseases occurred following an overly active inflammatory system (See #1)

 

  1. Complexity is at the basis of our adaptability, vitality, and longevity.

Nature is an example of how our system is adaptable.  We are composed of specialized cells and multiple systems that accomplish the task of keeping our bodies alive and functioning. The various iterations of our complex structure provide an incredible surface area within organs such as o/ur lungs, kidneys, intestines, vascular system, and brain.

 

  1. With age and disease comes a change from complex to a simpler structure.

Disease begins at the cellular level.  Multiple changes unfold and build-up to manifest the changes of aging that we see, including skin changes, hormonal changes, bone changes, and organ changes.  The process of aging shifts our bodies from a more complex system to one that is less complex. As the structure simplifies, the function declines.

 

Recommendations to Leverage Homeostasis

Optimal health leads to optimal lifespan and healthspan.  It is estimated that Eighty percent of longevity is environmentally related; twenty percent is genetics. Maybe what is less clear is that homeostasis is regulated by encoding various proteins from DNA, clearance of harmful waste products, absorbing old cells,  and propagating new ones. In that sense, it is all in genetics.

Below are some tips for living for longevity by leveraging homeostasis:

  1.  An optimal diet is one that does not induce inflammation: mostly vegetable intake which is high in fiber, to decrease rapid absorption of glucose. Avoid foods high in simple sugars or ultra-processed foods. Go natural.
  2. Physical fitness through daily, regular exercise.  Our bodies are designed for movement, moderately and regularly.
  3. Get good sleep, the same duration and schedule. As we age, sleep duration and efficiency declines. Sleep deprivation from sleep apnea and insomnia leads to the activation of the HPA axis (activates the sympathetic system with cortisol, epinephrine, and norepinephrine), leading to decreased metabolic, psychological, and immunologic resilience, as well as risk for diseases such as high blood pressure, atrial fibrillation, and diabetes
  4. Healthy environment.  The air we breathe in immediately interacts with our vascular system.  Pollution leads to “danger” substances being absorbed into the circulatory system, which induces inflammation.  One result is accelerated atherosclerosis (hardening of the arteries) and increased risk of endocrine, certain rheumatologic diseases and cancer. A healthy environment also means plenty of open space for reflection and tranquility.
  5.  Peaceful state, resilience, emotional intelligence, and mindfulness. Neuroplasticity relates to the ability of the brain to develop new neural connections for growth. Our daily behaviors essentially create a static series of neurotransmitters to essentially create an efficient pattern for the brain to interact with the environment.  The brain attempts to maintain this efficiency, even if it leads to repeating harmful behaviors as it interprets a new input using past experiences. Essentially, we relive prior traumas or negative experiences, create a stress response, and miss out on a way to get closer to the actual truth of the experience. Emotional intelligence entails understanding that the mind casts illusions and can influence interactions.  A person with high emotional intelligence doesn’t take things personally, shows collaboration, and seeks to understand.  Resilience is “bouncing back” after the experience of hardship, which can take the form of an illness, disease state, or brain-generated stressor.
  6. A substance-free life. Smoking, alcohol, and drugs (even caffeine) trigger various responses that lead to inflammation. They also create link a person to repeating use, the development of tolerance, and increasing harm.
  7. A social network. Humans are social beings.  Support systems assist in those experiencing stress or challenge.  People that collaborate and support one another are more likely to live longer. Married men live longer than their counterparts. If you are female, you might just live longer single.  As for longevity, ninety percent of supercentenarians (110) are women.

 

Hope you enjoy the article.  Remember that you can control your lifespan day-by-day, making positive health decisions. My best wishes to you on your journey. If you liked this article, please share it.  Thanks.

 

Bibliography

Harman D. The aging process. Proc. Natl. Acad. Sci. Vol 78, No 11, pp 7124-7128.

Hayflick L. Entropy explains aging, genetic determinism explains longevity, and undefined terminology explains misunderstanding both. PLoS Genet. 2007; 3: e220.

Mandsager K, Harb S, Cremer P.  Association of Cardiorespiratory Fitness with Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing. Cardiology. October 19, 2018.

Palmer AK, Gustafson B, Kirkland JL, Smith U. Cellular senescence: at the nexus between aging and diabetes. Diabetologia. 2019; 62 (10): 1835-1841.

Schoenhofen EA, Wyszynski DF, Andersen S, et al.  Characteristics of 32 supercentenarians. J Am Ger Soc. 2006l 54: 1237-1240.

Shah, Richa. Amoeba Proteus: Habitat, Structure, and Metabolism.

Wickens AP. Ageing and the free radical theory. Respir Physiol. 2001. Nov 15; 128(3):379-91.

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Luiz Presso
Luiz Presso