A Primer on Longevity Research: A Review of The Prospects of Curing Aging

Can aging be solved to extend our healthspan? A primer on longevity research and a review of the literature is now available for a general audience.  This detailed information can lead to better health knowledge and health improvement by the reader.  Check it out here:     https://bit.ly/2MD7k53    and below.

The mysteries of aging and how to control it have been among the greatest unsolved enigmas of history. The quest for the fountain of youth has been around since time immemorial. Pharaohs,emperors, and kings have placed this on their must find list but to no avail. Writing in Records of Investigation of Things, Zhang Hua of the Jin Dynasty in China ( 265–420) wrote: “ The less one eats, the broader the mind, and the longer the lifespan; the more one eats, the narrower the mind, and shorter the lifespan.” Can aging be cured? Modern science is now coming close to solving the puzzle of aging. The goal of this review is to translate highly technical medical research on longevity for a broader general audience. Definition of many terms can be found in the glossary at the end followed by references.

Dramatic changes over the past century have resulted in a massive increase in lifespan reaching 78.7 years in 2011. Between 1935 and 2010 the risk of dying has decreased by 60%. The discovery of penicillin by Fleming in 1928 is one factor in this lowered risk. The US in 1950, 11% of the population was 65 or older. This was the highest percentage 65 and older for any country in the world. By 2050 the percentage could reach 38%. Globally, age-related diseases like cancer, heart disease, and dementia are attributable to 100,000 deaths per day. Billions of dollars are spent on end-of-life healthcare. Recent research suggests that biological aging may be preventable. Dr. Cynthia Kenyon studying the roundworm Caenorhabditis elegans (C. elegans) was able to double their lifespan by changing a single letter in their genetic code. Can this be done in humans? This cannot be done yet but perhaps in the near future this will be a reality.

Global Aging

A silver tsunami is heading our way. As global populations age, an enormous strain will be placed on the healthcare system. Alzheimer’s disease, hypertension, lung disease, heart disease, and cancer will overwhelm us if there are no breakthroughs in longevity research to solve aging for the general population. Rather than focusing on specific diseases like cancer, the focus should be on geroscience extending healthspan. Healthspan is lifespan without the occurrence of age-related diseases.

For research funding to be diverted to solving aging, the FDA has to recognize aging as a disease. This would allow and fund clinical trials with interventions that can slow down or reverse aging. Metformin, the widely used type II diabetes medication, is the first antiaging clinical trial approved by the NIH.

Over 100 million Americans are over the age of 50 years. This is a market that is third in the world with over seven trillion dollars in market activity. They will need health care in the coming decades. The population of the US and the world retirees is increasing. China will have 200 million over 65 years by 2030. The most expensive healthcare occurs in the last one or two decades of life. The goal of the National Institute of Aging is to compress morbidity and extend healthspan. This is necessary to prevent a health crisis in demographic aging. This global crisis can be averted. George Church, a professor of genetics at Harvard says, “ my lab is not concerned with diseases of aging, which are effects rather than causes; it’s trying to get at the causes of aging and reverse them.”

The annual cost of health care related to obesity ranges between 70 and 100 billion dollars. Obesity leads to a rapid increase in diabetes with further cost increases treating complications like heart disease, stroke, renal failure, and blindness. Public health interventions that will reduce these conditions will be necessary to extend the healthspan of the population.[1]

Theories of Aging

There are several theories of aging that attempt to uncover the mysteries of longevity. There are two current categories, one is programmed aging, and the other is damage-based aging. In the programmed category there are three subcategories. 1) Programmed longevity. This is the result of the up-regulation and down-regulation of specific genes associated with cellular senescence. 2) Endocrine Theory. Hormones regulate aging, and the insulin-like growth factor 1 (IGF-I) pathway plays a key role. 3) Immunological Theory. During the aging process antibodies lose their effectiveness reflecting a decline in the immune system.

The second category of aging theories is based on the accumulation of damage to the body and metabolic errors. 1) Wear-and-Tear Theory. Analogous to the old automobile, cells, and tissues wear out resulting in aging. 2) The Rate of Living Theory. The antagonism of growth to healthspan via the mTOR pathway and the rate of oxygen basal metabolism results in a short lifespan. 3) Cross-Linking Theory. Cells and tissues are damaged by cross-link proteins that slow down bodily processes. The outcome is aging. 4) Free Radical Theory. Macromolecular components of cells are damaged by free radicals including superoxide. The function of an organ can collapse.[2]

Biomedical Gerontology

Learning the causes of aging is imperative to solve aging. There are avenues of intervention that are showing early promise. 1) After learning the cause of aging, we can develop interventions that stop the damage of aging. General protective drugs such as calorie restriction(CR) mimetics, antioxidants, and anti-inflammatory ones can be found. Nanotechnology offers promise. Buckyballs, a unique structure of carbon molecules can fight viral infections systemically, stimulate the immune system, and extend the lifespan of mice. Molecules in the blood of young rodents can rejuvenate the heart muscles and the brains of older rodents. 2) The second approach is to maintain and repair the damage that occurs to cells and organ systems in the body. The primary example for this approach is stem cell therapy. Neurodegenerative diseases are prevented by stem cells. When science can transform mature cells to stem cells, these are called pluripotent stem cells. When this technology is perfected, these modalities of treatment will advance rapidly. Another technique to fight aging is to use 3D printing to replace aging organ systems. Entire organs are replaced, analogous to maintaining a vintage car by replacing its worn out parts.

Recent research has determined that 1) animal models including mammals can have delayed aging from genetic intervention and small molecules; 2) in eukaryote cells, age delaying pathways are partially conserved; 3) most chronic diseases are caused by aging.[3]

Hallmarks of Aging

What are the cellular and molecular hallmarks of aging? To qualify as a hallmark each one should 1) occur during normal aging; 2) aggregating a hallmark experimentally should accelerate aging; 3) experimentally blocking or mitigating a hallmark should increase healthy lifespan.

Aging is a process that causes the deterioration of form and function of a living organism. The aging factors are multiple and include loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intracellular communication, genomic instability, telomere attrition, and epigenetic alterations.[4],[5]

Genomic instability is the first hallmark of aging. This is simply the accumulation of genetic damage of a lifetime. DNA repair is critical to maintaining physiological function. However, this repair efficiency declines with age in both the nucleus and in mitochondria.

The second hallmark is telomere attrition. Telomeres on chromosomes are analogous to the ends of shoelaces. Telomeres are shortened with age. Telomerase can repair telomeres and delay aging. Telomerase deficiency leads to diseases of old age.

Another hallmark of aging is epigenetic alterations. These include alterations in DNA methylation patterns, post-translational modification of histones, and chromatin remodeling. Epigenetics is the study of changes in organisms caused by modifications of gene expression rather than alterations of the genetic code itself.

The loss of proteostasis is another hallmark and involves impaired protein homeostasis. Misfolded proteins and aggregated proteins are examples. Genetic manipulation can improve proteostasis. Heat shock proteins (HSP 70) can, through proteostasis, preserve muscle function and extend health span. Proteostasis is defined as “competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell.”[6]

The somatotrophic axis in mammals consists of growth hormone and (IGF — 1). The insulin and IGF — 1 signaling (IIS) is the most conserved age controlling pathways in evolution. IIS participates in glucose sensing. AMP kinase, mTOR, and sirtuins are additional nutrient sensing systems. mTOR senses high amino acid concentrations. AMP K senses low energy states from CR. Sirtuins also sense low energy states. Down-regulation of mTOR extends lifespan in yeast, worms, and flies.

The respiratory chain which occurs in mitochondria degrades with age. The Free Radical Theory of aging suggests that this change is a result of increased production of reactive oxygen species (ROS). Mitochondrial dysfunction from ROS is possibly the primary cause of aging. Mitochondria are subcellular components that supply energy to cells such as muscles.

Cellular senescence, another hallmark, is defined as the cells which cease to divide, arresting the cell cycle irreversibly. Hayflick discovered that cells replicate about 50 times before senescence. These cells exert tumor suppression effects initially, but their accumulation leads to harmful inflammation and pro-aging effects. Senescence can be both positive and negative for healthspan. Initially, they are protective and later as they accumulate without clearance by the immune system or by autophagy they become harmful, primarily through inflammation.

When tissues decline in their regenerative capacity, aging ensues. A classic example is an important process affecting blood cell formation (hematopoiesis). This diminished production of adaptive immune cells results in a weaker immune response. This phenomenon of stem cell attrition is found in all types of stem cells, resulting in aging progression. Stem cell rejuvenation offers hope in slowing aging down or reversing it.

Aging occurs when immuno-surveillance against pathogens and premalignant cells declines. This is partially caused by altered intercellular communication, another hallmark of aging. Pro-inflammatory tissue damage accumulations initiate inflammaging (chronic inflammation) and aging. The consequences of this degradation of the signaling between cells in the tissues is the last hallmark of aging. [7]

Why are these hallmarks important to understand in depth with more research? This knowledge will open the gates to a myriad of avenues to intervene to slow the aging process and, moreover, potentially to reverse it. At minimum, we can expect an extension of healthspan as a return of investment into these avenues of research.

Caloric Restriction (CR)

Caloric restriction (CR) is the only proven method to extend longevity. The amount of food consumed affects the rate of aging. Fewer calories causing delayed aging was first confirmed in a rodent model in 1935 by McCay et al. [8],[9] CR is defined as the reduction of energy intake without malnutrition. CR is the most effective method to delay the development of age-related disease and the progression of aging in general. CR extends the lifespan and healthspan of numerous species.[10]

The objective of CR is to activate all the evolutionarily conserved longevity and aging regulators. During the 200,000-year evolution of Homo sapiens, metabolic mechanisms were established to protect the body and the mind doing the periods of famine. During our nomadic existence, there were periods after successful hunts that we could feast on our catches. Between these periods food was scarce or nonexistent. Evolution produced protections, particularly protections for humans to keep the brainpower to find the next food source. In modern society, these ancient metabolic pathways are not activated because we have feast only and not famine. CR is a way to activate these pathways by deliberately reducing our caloric intake. There is clear evidence that there are hundreds of genes linked to aging that have been evolutionarily conserved in many species including mammals.[11],[12],[13]By practicing CR, we can benefit from normally dormant mechanisms that convey huge benefits to our bodies and our minds. Let’s look at these protective strategies that the body has in its archives.

There are several key metabolic pathways activated or deactivated under the stress of low caloric intake. A phenomenon called autophagy is induced. Certain genes are activated under stress.

CR is a non-genetic and non-pharmacological intervention that extends lifespan in species from yeast to primates. CR modifies insulin sensitivity, inflammation, autophagy, oxidative stress, energy metabolism, neuroendocrine function, and hormesis response induction. Molecular signaling pathways mediating antiaging effects include: sirtuins, mTor, AMP- kinase, IGF-1, and PG 18[14]. CR in humans conferred the same benefits as seen in other species models such as reducing the metabolic and hormonal factors associated with type II diabetes, cardiovascular disease, and cancer.[15] CR extends longevity, both median and maximum lifespan, in the following species: S. Cerevisiae, C. elegans, D. melanogaster, rodents, rotifers, silkworms, spiders, fishes, dogs, and rhesus monkeys.[16],[17],[18]

The most effective interventions to regulate longevity focus on four cellular processes, nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Age-related diseases are expected to double over the next decade. Obesity and hypertension represent significant risk factors for strokes and cardiovascular disease.[19]

CR promotes increased mitochondrial function in skeletal muscle in the non-obese humans. This is a favorable outcome of CR and CR mimetics. CR for the long-term increases the maintenance quality of skeletal muscle.

Moderate CR in humans mitigates several metabolic and hormonal factors that are linked to the disease progression of type 2 diabetes, cardiovascular diseases, cancer, and major health problems.[20] Healthspan is improved by a reduction of caloric intake. Cardiovascular function is improved from the delayed aging.[21],[22]

CR requires optimal nutrition

Micronutrients are cofactors for enzymes. There are 30 essential vitamins, minerals, and fatty acids that we need for micronutrients. These are all the percentages of people who are deficient in those micronutrients. The percent of the American population below the Estimated Average Requirement (EAR) for vitamins A (34%), C (25%), D(70%), and E(60%), calcium (38%), and magnesium (45%). Only 3% of the population for potassium and 35% for vitamin K had total usual intakes greater than the EAR.

What are the consequences? They are subclinical effects which means that you will not notice them as you would if there were macro clinical effects like scurvy from a complete deficiency of vitamin C. Survival pathways get priority for micronutrients and this is called the triage theory. For example with vitamin K, blood clotting is a priority whereas repairing damage to DNA is a secondary priority. In the long run, DNA damage will advance aging. Mice will get diseases of aging if you knock out the genes associated with removing calcium. They die early but not immediately.

Magnesium is another important micronutrient that is responsible for 300 biological functions in the body. The RDA for magnesium is 300 to 400 mg daily. To make and use ATP, magnesium must be bound to ATP. Magnesium will repair damaged DNA and enzymes need magnesium. Reactive oxygen species (ROS) from metabolism causes cell DNA damage. Magnesium is needed by 500 enzymes in the body.

Vitamin D and the two marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) modulate serotonin synthesis, release, and actions in the brain. The enzyme tryptophan hydroxylase 2 converts tryptophan to serotonin when Vitamin D is present. Serotonin has a role in regulating social behavior, impulse control, sensory gating, decision-making, emotions, aggression, anxiety, and memory. DHA allows serotonin to be released from presynaptic to synaptic neurons. Therefore, omega 3s and vitamin D are important to optimal nutrition. Folic acid deficiency can cause chromosome breaks like radiation. Micronutrients are very important because 22% of all enzymes require cofactors that are found in micronutrients. [23]

 

Nutrient Sensing Metabolic Pathways

Nutrient sensing is the cells ability to sense and respond rapidly to changes in environmental nutrient levels of fuel substrates such as glucose, lipids or amino acids. Nutrient scarcity has influenced the evolution of cells and their metabolic processes. A deeper understanding of nutrient sensing will be critical to designing interventions against human diseases.[24]

Adenosine Monophosphate-Kinase pathway (AMPK)

CR and CR mimetics activate AMPK which stimulates SIRT1( see below) via an increase in NAD+ levels. This leads to mitochondrial biogenesis. CR modulates AMPK and mTOR signaling resulting in mitochondrial protective benefits. [25],[26],[27],[28] CR increases AMPK expression by changing the AMP/ATP ratio in mitochondria and increasing mitochondrial biogenesis and promoting insulin sensitivity. AMPK is a sensor of intracellular adenosine nucleotide levels. AMPK is activated when ATP production is low with corresponding increases in AMP and ADP. AMPK promotes pathways to increase ATP. Prolonged exercise and low nutrients can also activate AMPK. The most potent pharmacological agent to activate AMPK is metformin.[29]AMPK activation is protective of healthspan.

Mechanistic Target of Rapamycin pathway (mTOR)

The mTOR pathway is instrumental in initiating growth. It detects and responds to caloric intake, environmental stresses, and growth factors. In humans, mTOR has two forms, mTORC1 and mTORC2.[30],[31],[32],[33]Protein translation and cell growth are induced by activated mTORC1. When mTORC1 is inhibited, growth stops and a stress response begins as autophagy.[34] The mTOR activity inhibits autophagy, which is the major lysosomal degradation pathway that re-cycles damage and harmful cellular material. The reduced mTOR signaling reduces protein synthesis, and promotes autophagy, leading to life extension effects in multiple species.[35]

Silent Information Regulator (Sirtuins)

Sirtuins are defined as “a type of protein involved in regulating cellular processes including the aging and death of cells and their resistance to stress.” The seven evolutionarily conserved mammalian genes that code for sirtuin proteins are involved in at least 24 molecular and cellular functions that are beneficial to mammals. The sirtuins, in particular, SIRT1, SIRT3, and SIRT6 suppress a spectrum of age-related pathologies. When these and the other sirtuins are upregulated, they play a role in promoting mammalian health. SIRT1 functions in transcription silencing, mitochondria regulation, insulin signaling, tumorigenesis, apoptosis, cell proliferation and survival, tissue regeneration, differentiation, and stress response. NAD+ can activate SIRT1, but it declines with age. Replacing NAD+ with precursor supplements is theorized to slow aging and promote health span.[36] SIRT3 functions in fatty acid oxidation, TCA cycle, oxidative phosphorylation, and oxidative stress. SIRT6 functions in genome stability, and telomere silencing.[37]

Mitochondria

Mitochondria, the energy component of cells has a key role in aging. When mitochondria breakdown from decreased oxidative capacity and damage, aging advances. One theory of aging is based on damage accumulation in cellular molecules from toxic reactive oxygen species (ROS). This leads to mitochondrial dysfunction and the ticking of the aging clock. Our goal is to protect and promote mitochondrial efficacy and biogenesis.[38] Genetic approaches have led to hundreds of aging related genes and strong evidence of evolutionary conservation among longevity pathways between numerous species, including mammals.[39] When mitochondria are impaired ROS generation increases, and antioxidant defenses decrease. This leads to mitochondrial DNA damage.[40],[41] Impaired mitochondria cause accelerated aging and higher mortality.

IGF-1 Pathway

CR inhibits Growth Hormone/ IGF-1 signaling and is linked to increased autophagy, reduced mTOR signaling, reduced plasma glucose, increased hepatic insulin sensitivity, and increased resistance to oxidative stress. IGF-1 has growth-promoting effects on body growth and most cells in the body including: nerve, skin, bone, liver, kidney, skeletal muscle, cartilage, lung, and hematopoietic cells. Growth hormone from the pituitary gland reaches the blood stream and stimulates the liver to produce IGF-1.[42] Fifteen percent CR confers benefits against mortality, and it reduces IGF-I and growth hormone.[43],[44]

A five day fast lowers IGF-I plasma levels by more than 60% and increases IGFBP-1, an IGF1 inhibiting protein. The lowering of IGF-I through glucose control is an anti-aging regimen.[45] Controlling blood glucose levels is one of the most important healthspan promoting measures.

Nrf2 pathway

Sulforaphane activates the Nrf2 pathway, a master regulator that affects the expression of over 200 genes including: antioxidant proteins that protect against oxidative damage triggered by injury and inflammation. Glucoraphanin is its precursor. Myrosinase is an enzyme which converts Glucoraphanin into Sulforaphane. Sulforaphane activates phase 2 detoxification enzymes. For example, glutathione S transferase conjugates xenobiotic metabolites and provides chemo-protection. It’s also very important for producing hormetic stress-induced heat shock proteins. Heat shock proteins perform a chaperone function to stabilize new proteins to ensure correct folding and to refold damaged proteins. The Nrf2 pathway prevents cancer, it deactivates carcinogens, deactivates genes of inflammation, and activates anti-oxidative genes. Nrf2, slows aging by reducing oxidative stress and DNA damage. It restores the adaptive immune response. Sulforaphane crosses the blood-brain barrier and has potent anti-inflammatory effects for neurons.[46] This phytonutrient is found in cruciferous vegetables such as Brussel sprouts, broccoli, cauliflower, bok choy, kale, collards, arugula, broccoli sprouts (contain 100X the sulforaphane found in broccoli), Chinese broccoli, broccoli rabe, kohlrabi, mustard, turnip, radish, watercress, and cabbage.

FOXO Pathway

Hydra are a marine species that has immortality. They have an abundant supply of stem cells and high levels of FOXO gene expression. The FOXO transcription factors activate genes that promote tissue and cellular renewal and rejuvenation. FOXO maintains stem cells and is linked to human longevity. Across ethnicities, FOXO is found in many centenarians.[47],[48]The FOX03 longevity pathway is helpful in keeping inflammation low and is a major factor in living to be a centenarian. It is also associated with prolonged physical functionality and cognitive abilities.

CR Mimetics

There is a quest underway to find molecular agents that can activate the same protective pathways that are activated by CR. These agents are called mimetics. Their discovery would obviate the need to reduce calories in the diet.

Spermidine is a polyamine that induces autophagy. Most importantly, it promotes neuronal autophagy in the brain. It inhibits neurodegeneration and amyotrophic lateral sclerosis (ALS). It reverses age-associated memory loss in flies. It is involved in activation of phylogenetically conserved aging regulators SIRT2, a NAD+ dependent histone deacetylase, promotes longevity. Epigenetic hypoacetylation of histones is key to healthy aging. Acetyl transferase is inhibited by spermidine and induces autophagy. It removes the S groups from proteins. It increases the deacetylases such as SIRT 1, and it results in less protein acetylation and increases autophagy.

Resveratrol stimulates autophagy. Resveratrol is a polyphenol that prolongs the lifespan of flies, worms, and mice. It offers protection against age-associated diseases, insulin resistance, cardiovascular disease and type II diabetes., oxidative stress in the heart, and degeneration. Resveratrol shows a similar pattern to gene expression stimulated by CR in the following tissues: neocortex, liver, skeletal muscle, heart, and adipose.

Rapamycin strongly induces autophagy and extends lifespan in yeast, flies, right worms, and mice. It’s potent in immunosuppressive properties preclude it from being a life extension agent for humans. Rapamycin extends the lifespan of mice, however, it presents a risk to humans.[49],[50]

Metformin is a biguanide derived from the lilac plant that activates the AMP-kinase pathway. Metformin decreases glucose production in the liver, increases glucose uptake in peripheral tissues and activates usage of fatty acids. It has also been identified as an anti-cancer agent. There are similar changes in protective gene expression as seen in CR with metformin. Metformin has increased the lifespan of C. elegans. The enzyme promotes energy balance and is involved in glucose and fat metabolism. Metformin inhibits mTOR which is involved in the control of cell proliferation and tumor growth. Metformin inhibits chronic inflammation. Metformin affects on transcription mirrors that of CR on transcription regulatory pathways. Metformin extends lifespan in mice and it mimics the outcomes of CR.[51]

Nicotinamide adenine dinucleotide ( NAD+) NAD+ is a coenzyme that serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions and a cosubstrate for enzymes such as sirtuins. NAD(+) declines with age thus compromising the function of mitochondria, the energy factory in cells.[52] NAD + improves mitochondrial function. It can reduce oxidative stress, protects DNA synthesis, and suppress tumor growth. NAD helps to reprogram dysfunctional cells and can increase cognition and prevents Alzheimer’s disease.[53]

Various Longevity Issues

Autophagy

CR induces autophagy, a catabolic process that breaks down cellular components and recycles them. They eliminate senescent cells that cause inflammation. Energy levels are maintained, and sirtuins are expressed. These are the anti-aging effects of CR.[54],[55],[56] Senescent cells can cause inflammation. Ideally, the body should get rid of the cells. Exercise is a good method to achieve this. Exercise decreases the risk of: cardiovascular disease, diabetes, hypertension, stroke, disability, and minimizes risk in general. Fasting is an important tool that we have evolved with. Fasting promotes autophagy. Apoptosis will help get rid of senescent cells.

Hormesis

It is thought that CR functions as a mild stressor that up-regulates protective mechanisms against aging. This is the hormesis hypothesis.[57] Hormesis is defined as an “adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals.” The key to hormesis benefits are the cytoprotective effects it confers.[58],[59],[60]

Hormesis works when we respond to stress. It promotes robustness. We want to bulletproof the brain against inflammation. The definition of resilience in aging is cognitive reserve. People who have early rich experiences in life are safer in old age because of increased cognitive capacity. Hormesis benefits the body.

An example of this is a sauna with dry heat. The benefits include: sensitizes the brain to endorphins, improves cardiovascular health, improves overall longevity, increases heat shock proteins, activates FOXO3 gene, and increases growth hormone that improves the repair of muscles. Hyperthermic conditioning promotes the development of heat shock proteins (HSP). These proteins repair protein folding problems. Recent research on sauna use has discovered the mechanism is based on the production of heat shock proteins, immune and hormonal pathway changes, increased bio-availability of nitric oxide to vascular endothelium, and excretions of toxins through sweating.[61] The saunas types use infrared heat that reaches 45–60° Celcius and the Finnish heated rock system that reaches 80°–100°Celcius. Typical periods in the sauna are 20-minute intervals.

Cold stress benefits by increasing norepinephrine and helps to reduce depression. It increases focus, attention, vigilance, and mood. The colder the water the greater the norepinephrine/ epinephrine release. The cold also increases mitochondrial biogenesis in adipose tissue. There is a browning of the fat that protects against cold. Exposure to 16°Celcius leads to a 37% increase in mitochondrial biogenesis.

Biomarkers of Aging

Biomarkers of physiological function include: lung function, cardiovascular function, glucose metabolism, bone mass, and skeletal composition. Blood lipids and high blood pressure are associated with higher cardiovascular morbidity and mortality. Bone mass declines with age and predicts fractures and mortality. Low skeletal muscle predicts functional decline and high Body Mass Index ( BMI) predicts higher mortality and shortened healthspan.

Neurodegenerative diseases are the end result of cognitive decline. The biomarkers are linked to three domains: executive function, episodic memory, and processing speed. Various tests are used to assess these domains. Cognitive decline can begin as early as 45 years of age.

The hormones estrogen, testosterone, DHEAS, and growth hormone are linked with premature mortality and physical decline.

Immunosenescence reflects a decline in immune function as we age. There is an age-related increase in systemic inflammatory cytokines. High plasma concentration of IL6 and TNF-α are linked to lower gait speed and lower grip strength. As the immune risk profile declines with age, there is an association with increased mortality. Some of these classic immune declines are not seen in centenarians. However, they do show some inflammaging.[62]

Retinal nerve fiber layer (RNFL) thickness is a biomarker of vision changes. RNFL decreases in thickness significantly with advancing age in a study of 3 years of 25 adults using spectral optical coherence tomography/scanning laser ophthalmoscope (OCT/SLO). [63]

Benefits of Exercise

Aerobic exercise in moderation such as walking, cycling or swimming attenuates age-related decreases in cardiorespiratory fitness. Resistance training involving weightlifting or resistance bands improves muscle mass. Greater than 450 min/ wk of moderate to vigorous exercise is associated with longer life expectancy. Physical inactivity globally is a public health crisis.

In a study where a walking group was compared to a sedentary group, the walking group showed a 7.8% increase in VO2 MAX, a 2% increase in hippocampal volume, improvement in spatial memory, and increases in brain derived neurotropic factor ( BDNF). In a 24-week intervention study of 150 min of moderate exercise 3 days a week for 18 months with 150 respondents aged 50 and above, the intervention group showed significant improvement in cognitive function. During incremental exercise, the maximum rate of oxygen consumption is called VO2 MAX.

VO2 MAX is a strong and independent predictor of longevity along with all-cause and disease-specific mortality. This reflects the cardiorespiratory fitness of the individual. Rowers and cyclists have the highest recorded VO2 MAX because of the rigor of these sports.[64],[65],[66] A major challenge for the health care system is to maximize the functional capacity of the elderly. The most common measure of functional capacity is the VO2 MAX measure. This capacity declines 20–25% per decade in those over 70 years.[67]

Optimizing CV fitness can generate huge health benefits. High-intensity interval training (HIT) can provide CV benefits efficiently. Endurance training combined with HIT can lead to improvement in VO2 MAX. Research indicates that HIT provides greater gains than endurance.[68]

Sleep

Sleep is an essential component of good health. There are several aspects of sleep that contributes to good health outcomes. The definition of sleep health is defined as: Sleep health is a multidimensional pattern of sleep-wakefulness, adapted to individual, social, and environmental demands, that promotes physical and mental well-being. Good sleep health is characterized by subjective satisfaction, appropriate timing, adequate duration, high efficiency, and sustained alertness during waking hours.[69]

Patel et al. have found that 6–7 hours sleep corresponds to cardiac health and longevity.[70]

Restoration, healing, and removing of metabolic waste occurs during sleep. This happens during slow wave sleep when the body temperature is lower, along with a lower heart rate and brain oxygen consumption. Metabolism is lowered. The brain is specially benefited and requires sleep to restore while the rest of the body can also be restored during quiet wakefulness.[71]

Happiness

Happy people have longer healthspans. In a recent study, those who are pretty happy have a risk of death that is 6% more than those who are very happy. Those who are not happy have a 14% higher risk of death. Happiness is linked to other risk factors like social relations, religion, and socio-economic status.[72]

In the new science of positive psychology, the acronym P.E.R.M.A is a Theory of Well Being and stands for pursuing Positive emotions, Engagement, Relationships, Meaning, and Achievement. Martin Seligman at the U of Penn defines happiness as “positive emotion, engagement, and meaning.” The trail to happiness begins with increasing positive emotion by cultivating gratitude and forgiveness of the past; increasing our positive emotions of the present through savoring and mindfulness; and increasing our positive emotion about the future by building hope and optimism. Happiness involves pursuing gratification through engagement. In this engagement, we are totally absorbed in some creative task or simply reading a book. The third route to happiness is through seeking meaning and purpose in life. This purpose later leads to a sense of accomplishment. Having positive relationships with others is also a major route to happiness.[73],[74]

 

Social Connections and Health

When mammals are threatened with survival from predators or injuries a coordinated physiological response occurs that increases the chances of survival. Researchers have observed that social connections are key to maintaining optimal health. There is a strong association between social ties and health. Those who live alone with poor social networks have a greater risk of poor health. The importance of social connections for mammalian survival have evolved in the brain a survival response to threats to social connection. Activation of the sympathetic nervous system (SNS) for flight or fight and the hypothalamic -pituitary -adrenal (HPA) axis stress response can occur when someone is rejected by a social group. Social support on the contrary activates neural regions that process safety signals and inhibits a stress response.[75]

In an intervention study, positive social connections, positive emotions, and physical health all benefit each other in a synergistic, upward, and self-sustaining spiral.[76]

Brain Health

Brain-derived neurotrophic factor (BDNF) is a very important neurotrophin that supports the survival of existing neurons and promotes the growth and differentiation of new neurons and synapses. It is active in both the central and peripheral nervous system. It is active in areas vital to learning, higher thinking, and memory including: the basal forebrain, cortex, and hippocampus. Areas outside the brain of action include: kidneys, prostate, retina, motor neurons, and saliva.[77]

In comparison to the rest of the body the brain consumes significantly more energy. How food energy is transferred to neurons is vital to control of brain cognitive function. BDNF is related to energy metabolism and synaptic plasticity. BDNF is more highly concentrated in areas of the brain associated with cognitive and metabolic regulation. These are, respectively, the hippocampus and the hypothalamus. The omega three fatty acid DHA in the diet increases levels of BDNF in the hippocampus and elevates cognition.

In contrast, epidemiological studies indicate that junk food such as trans fat, sugar, and saturated fat adversely affect cognition. After junk food for three weeks in a rodent model, BDNF levels in the hippocampus is decreased. Furthermore, excess calories in the diet reduce synaptic plasticity and increases the risk of cell damage. Moderate CR can protect the brain by reducing oxidative damage to cellular proteins, lipids and nucleic acids.

Research indicates that diet and exercise can positively alter brain health. Dietary manipulation offers an opportunity to protect the brain and enhance cognitive function. Excess calories in western countries, leading to obesity and diabetes, could be as harmful as the lack of enough calories in poor countries.[78]

Certain nutrients can help safe guard brain health. Multiple studies in a systematic review indicate that omega-3 fatty acids can protect against neurodegeneration in the elderly.[79]

Harvard health suggests 12 ways to maintain brain health:

1. Get mental stimulation
2. Get physical exercise
3. Improve your diet
4. Improve your blood pressure
5. Improve your blood sugar
6. Improve your cholesterol
7. Consider low-dose aspirin
8. Avoid tobacco
9. Don’t abuse alcohol
10. Protect your head
11. Build social networks[80]

Microbiome

Commensal, symbiotic and pathogenic microrganisms share our body space and impact health and disease. These organism’s genes are 150 times more prevalent than the genes in the human body and live on our skin, inside our digestive track, and most places in the body. An unbalanced gut microbiome is called dysbiosis and is linked to inflammatory bowel disease, diabetes, allergies, asthma, autism and other conditions.

Recent research has revealed the interplay between the gut microbiome and the biology of the host. This suggests the possibility of manipulating the microbiome to prevent or treat disease. Metformin has extended the life of C. elegans by modulating bacterial folate metabolism. Research is early on this subject.[81]

The composition of gut microbiota is linked and integrated with aging and longevity. The microbiome can influence age-related processes like inflammation, oxidative stress, metabolic regulation, and energy homeostasis. Chronic diseases and aging can be delayed through use of probiotic supplements. In Drosophila probiotics increased longevity by 55%.[82]

Fasting

Ingesting minimal or no amounts of food and caloric beverages for periods of 12 hours to three weeks is fasting. Research has indicated that various forms of fasting can potentially help reduce weight, optimize health, and delay aging. Intermittent fasting (IF) can be twice-weekly or alternate day and periodic fasting(PF) which can last several days or longer, every fortnight are the two main types of fasting. A 12 to 24 hour fast can typically result in a 20% or larger decrease in serum glucose and a depletion of hepatic glycogen. During fasting, most tissues rely on fatty acids for energy. However, the brain relies on ketone bodies, beta hydroxybutyrate, and acetoacetate in addition to glucose for energy consumption. Severe food deprivation results in the decrease in the size of all organs except the brain. This points out how evolution has conserved thinking capacity as a priority during famines to insure the brain locating the next food source. Fasting for three days causes a 30% decrease in plasma insulin, glucose, and a decline in IGF-1. The research suggests that fasting during adult life can promote optimal health. There are robust fasting effects on increasing insulin sensitivity, lowering: blood pressure, body fat, IGF-1, insulin, glucose, harmful lipids, and inflammation. Fasting also protects cells from DNA damage, increase apoptosis of damaged cells, and suppress cell growth which suggests that cancers are prevented or retarded. Epidemiological data combined with centenarians and their diets can provide clues for early interventions including fasting to promote extended healthspan. [83] Time-Restricted Feeding (TRF) minimizes the time of feeding during the day to maximize fasting hours. TRF produces ketone bodies, namely beta hydroxy butyrate, thus promoting health span.

A health promotion strategy has to stress avoiding metabolic syndrome. This is a cluster of risk factors for obesity, diabetes, cardiovascular disease, hypertension, insulin resistance, and dyslipidemia. Fasting can help prevent metabolic syndrome in overweight persons. Advice from a provider should be sought before beginning fasting.

Age Reversal Breakthrough

Latorre et al. have recently reversed aging in vitro with human endothelial cells. Senescent cells accumulation in the body is a driver of aging. They are old cells that do not function as they should, and they adversely affect normal cells around them. The goal of the study is to remove senescent cells (senolysis) or to attenuate their phenotype (senostasis). In the study low levels of hydrogen sulfide, a cytoprotective gas was able to rescue some of the features of the senescent cells. There was a 50% drop in senescent cell load. This is mediated through the action of genes SRSF2 and HNRNPD and arecalled splicing factors. Splicing factors are proteins involved in the removal of introns from strings of messenger RNA so that the exons can bind together. Genes are turned off as we age, however, splicing factors can reverse this trend and promote healthspan.[84]

Longevity Escape Velocity

It has been proposed that the science of longevity will soon reach a longevity escape velocity. The accelerating rate of medical advances, and rejuvenation therapies will increase healthspan and give the individual additional years of life. These additional years will give the individual access to the next round of medical breakthroughs, thus adding more years to their lifespan. This means that the mortality rate is dropping every year. When the life expectancy increases as a result of sustained sequential medical breakthroughs, we have reached longevity escape velocity. We can summarize this as a bridge to a bridge to a bridge. Life expectancy is extended longer than the time of expected survival.[85]

Disruptive Technologies

Artificial Intelligence (AI) is a tool that will assist the antiaging cause. AI’s diagnostic capability exceeds physicians for some conditions like melanoma and other cancers. AI reveals through a technique called deep learning intricate structures and hidden information in large data sets. Algorithms on a multilayered neural network can tease out secrets the data may hide. The neural networks can imagine things similar to the human brain and can outperform humans in the interpretations of MRIs, CT scans, and ultrasound imaging.

Drug discovery is aided by AI. This will rapidly unveil new medicines that will slow and potentially reverse aging. AI can facilitate identifying longevity genes and make individualized medical care possible.

Robotic surgery will continue to improve in assisting human surgeons.

AI can discover senolytics that can eliminate senescent cells that persist in the body with limited function yet promoting damaging inflammation. This was mentioned under age reversal above. Some senolytics can indirectly reduce inflammation. Quercetin is an example of a senolytic. New CR mimetics will be discovered.

The compound-annual-growth-rate (CAGR) of artificial intelligence in health care is 42% and will reach $6.6 billion in 2021. AI will improve patient outcomes by using the complete knowledge of the medical literature and electronic health records (EHR)to assist providers in diagnosis and treatment. Chronic conditions will be diagnosed in minutes using an AI cognitive system. Cost of care will be reduced through better workflows and minimizing unnecessary tests and procedures.

Immunotherapy has the promise to transform cancer care. Immune checkpoint inhibitors are currently used to attack cancer cells. Chimeric antigen receptors, a newer technology, are engineered receptors that combine a new specificity for an immune cell to target cancer cells.

The ability to extract cancer cells from blood is a liquid biopsy and provides early noninvasive diagnosis and monitoring of cancer. This will be more effective than CT scans for detection of tumors.

Advancements in gene therapy is another breakthrough that is imminent. Genetic tools like CRISPR/ Cas9 can change genes and turn off damaging genes. CRISPR/Cas9 can make targeted modifications to DNA accurately, cost-effectively and reliably. This has the potential to cure genetic diseases. This can also modify the human genome. The bio-ethics of this action is important to consider by the medical community.

The rapid emergence of 3D printing will transform the ability to replace tissues and organs in the body. Scaffolds can be printed to serve as the framework for new organs. There are presently over 1 million people needing transplants globally. However, only 5000 people receive transplants.

In August 2018 De Fauw et al. reported in Nature Medicine in a study of deep learning for diagnosis and referral of retinal disease that artificial intelligence performed as well as two of world’s leading retina specialist with an error rate of 5.5%. The DeepMind team created an algorithm for the computer to analyse optical coherence tomography (OCT), a high resolution 3D scan of the retina. Thousands of OCT scans were used to train the computer using machine learning. This AI boost can facilitate early diagnosis and referrals which are key to preventing blindness.[86]

Medical advancements are on the horizon in these areas:

1. “Medication management
2. Medication information, reminder, tracking tools, and compliance services
3. Vital sign monitoring
4. Health sensors, diagnostic services, enabling technologies and solutions
5. Emergency Detection and Response
6. Home Sensors, PERS/fall detection, location tracking, activity monitoring
7. Physical Fitness
8. Fitness devices, apps, programs, enabling solutions
9. Aging with Vitality
10. Hearing and vision; preventive aging care; cognitive and brain health, and everyday tools and services
11. Diet and Nutrition
12. Nutrition content and education, diet and nutrition tracking tools, management programs, meal plan/delivery/cooking solutions
13. Behavioral and Emotional Health

Companionship solutions, support group community, behavioral modification/ self-help solutions, and stress/emotion management/therapies[87]”

 

Conclusions

The last 100 years have demonstrated a dramatic increase in the aging population. At birth, life expectancy has increased from 50 years in 1900 to 78 years in 2008. How can we dramatically improve the healthspan of this growing tide of the elderly? The science for this solution is linked to activating archived metabolic pathways through CR effects on the mammalian physiology.

Some of the basic knowledge of CR is over 75 years old. As more research unfolds detailing the underlying mechanisms of CR, the broader population can benefit. Eventually, this knowledge will result in controlling aging and increasing the healthspan in the elderly. [88]

CR and exercise are the two most common interventions to slow aging and increase healthspan. It is a race against time to avert an aging crisis that will overwhelm the health care system. CR mimetics offer the chance to acquire the benefits of CR while enjoying the calories.

The quest for interventions to reach healthy aging is the purpose of aging research. This will have major impacts on the current epidemics of obesity, diabetes, and hypertension.[89]

Targeting the pathways with interventions that are protective offer hope for increasing healthspan. These interventions include: CR practice, fasting, low glycine diet with protein restriction, inhibition of GH/IGF-1 signaling, inhibition of mTOR signaling, upregulating sirtuins, and activating AMPK. There is also promise in CR mimetics that provide pharmacological interventions that could with more research benefit the population writ large. These include: metformin, spermidine, statins, acarbose, Resveratrol, Rapamycin, and NAD+. The research evidence is accumulating for targeting aging linked pathways through various methods. The research community has decided to focus on treating age-related diseases and not the broader issue of aging just yet. [90] Soon the focus can be on nothing less than a cure for aging.

A blueprint to healthy aging includes: healthy diet, exercise, social engagement, meaning, and purpose. The blueprint is the acronym SHIELD which stands for sleep, handle stress, interaction, exercise, learn new things to increase your synapses, and diet which limits sugar and fat.

The prospects for the future are promising with the increasing focus on solving aging. This potential breakthrough has the potential of benefitting the health of all humanity regardless of class or economic status. Nature has through natural selection evolved protective metabolic pathways that mitigate aging. Modern science can teach us how to transform these protective pathways from dormancy to full activation benefiting the general population of all ages. Remember to stay beautiful.

Glossary

A non-exhaustive list of definitions of terms used in geroscience and longevity.

Aging: a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability. In humans, aging is characterized by a complex phenotype.

Apoptosis: The apoptosis is a genetically directed process of cell self-destruction that is marked by the fragmentation of nuclear DNA, activated either by the presence of stimulus, and is a normal physiological process which eliminates DNA-damaged, or unwanted cells, and when halted (for instance, by genetic mutation) it may result in uncontrolled cell growth and tumor formation called also cell suicide, and programmed cell death. Apoptosis, unlike necrosis, does not induce any inflammatory process (4)

Atherosclerosis: The atherosclerosis is the accumulation of lesions resulting from the deposition of cholesterol on the arterial walls, favored by circulating oxidized LDL cholesterol. (5)

Adenosine Triphosphate (ATP): The adenosine triphosphate is a molecule produced by mitochondria and composed of a nucleotide, adenosine triphosphate, which occurs in all cells where it stores energy in the form of high-energy phosphate bonds. (6)

Antagonistic pleiotropy: theory by George Williams that explains the existence of aging by the existence of genes beneficial early in life but harmful at later stages.

Autophagy: digestion of the cell’s own components; it has been implicated in aging.

Biogerontology: the scientific study of the biological process of aging.

Caloric restriction (CR): diet regime consisting of eating considerably fewer calories, without malnutrition, that has been considered as a potential method to delay aging.

Cellular or clonal senescence: see replicative senescence.

Cytokine: It is a peptide mediator which plays an active role in the immune and inflammatory signaling.

Deacetylation: This a chemical process that removes acetyl on a molecule.

Developmental theory of aging (DevAge): theory arguing that aging is an extension of developmental mechanisms.

Disposable soma theory: theory by Thomas Kirkwood that explains the existence of aging by the allocation of resources from somatic maintenance to reproduction.

DNA damage theory of aging: theory that argues that aging is due to the accumulation of DNA damage with ensuing cellular alterations and disruption of tissue homeostasis.

Endocrine system: group of hormone-producing glands and their secretions (hormones); the endocrine system have been implicated in aging.

Enzyme: An enzyme is natural protein produced by all living organisms (bacteria, plants and animals). They are biochemical catalysts which accelerate chemical reactions in cells and convert molecules into other ones.

Epigenetics: study of heritable changes in a phenotype that are not due to alterations in the DNA sequence but rather due to chemical changes of the DNA and associated proteins.

Free radical theory of aging: theory by Denham Harman that argues that aging is a result of damage accumulation caused by reactive oxygen species.

Gene: DNA sequence that encodes a protein and represents the basic unit of inheritance.

Genetics: the study of heredity — i.e., the passing of characteristics from one generation to another — and of variation of inherited characteristics. Aging has a strong genetic component.

Genomics: the study of an organism’s genome.

Genome: the full DNA sequence of an organism.

Geriatrics: the medical study of diseases and problems of the elderly.

Germ cells: the reproductive cells which contain the genetic material passed on to the offspring.

Gerontology: the scientific study of the aging process and old age. In the context of senescence.info, gerontology refers to the biological study of aging and old age, also called biogerontology.

Hayflick limit: the inability of cells to replicate indefinitely in culture.

IMR: initial mortality rate. The age-independent mortality rate obtained from the Gompertz equation.

Life expectancy: how long, on average, an animal can be expected to live. Can be used interchangeably with average lifespan and average longevity.

Life history: the changes organisms undergo from conception to death, focusing particularly on the schedule of reproduction and survival.

Lifespan: the period of time in which the life events of a species or sub-species (e.g., a strain or population) typically occur. Can sometimes be used interchangeably with longevity even though they have slightly different meanings.

Longevity: the period of time an organism is expected to live under ideal circumstances. Can sometimes be used interchangeably with lifespan even though they have slightly different meanings.

Maximum lifespan (tmax): the maximum period of time organisms of a given species or sub-species (e.g., a strain or population) can live. Usually refers to the longevity of the longest-lived individual of a given species or sub-species.

Mechanical senescence: age-related changes that are a consequence of mechanical usage.

Metformin: An oral antidiabetic agent that decreases the production of glucose in the liver and lowers plasma glucose levels. (39)

DNA Methylation: Process that adds a methyl group (-CH3) to any other molecule (40)

Microbiome: Community of microorganisms (such as bacteria, fungi, and viruses) that live in or on the human body.(41)

Mitochondria: Organelle within eukaryotic cells essential for breathing that produces adenosine triphosphate (ATP) which is the main energy molecule used by the cell. (42)

Mitogen: A mitogen is a substance that triggers the process of cell division. (43)

mRNA: Form of RNA, transcribed from a single strand of DNA. It carries the required genetic information for the protein synthesis from DNA to the ribosomes. (44)

MRI: A non-invasive imaging technology that produces three-dimensional detailed anatomical images without the use of damaging radiation. (45)

mtDNA: DNA that is contained in the mitochondria of eukaryotic cells and is inherited maternally. (46)

Mitochondrion: cellular organelle that produces most of the cell’s energy.

MRDT: mortality rate doubling time. The time required for the mortality rate to double. Inferred from the Gompertz equation.

Mutation: change in the DNA sequence of an organism or cell.

Mutation accumulation theory: theory by Peter Medawar that explains the existence of aging by the accumulation of mutations with harmful effects at later ages.

NAD (Nicotinamide adenine dinucleotide): A coenzyme involved in many cell redox reactions, including ATP synthesis. (47)

Neurogenesis: Process which generates functional neurons from adult neural precursors, and occurs throughout life in restricted brain regions in mammals. (48)

Nootropics: Nootropics are smart drugs or cognitive enhancers, supplements, or other substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals. (49)

Nucleotide: A group of molecules that, when linked together, form the building blocks of DNA or RNA.

Negligible senescence: organisms in which the aging process has not been detected in spite of detailed studies, as observed in some animals.

Oxidative stress: damage caused by reactive oxygen species; oxidative stress has been implicated in aging.

Proteome: Set of proteins expressed in a cell at any time (64)

Rapamycin: Bacterial macrolide with antibiotic and immunosuppressive activity and structural similarity to FK506. (65)

Reactive oxygen species (ROS): A type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell. (66)

Resveratrol: The resveratrol is a trihydroxy stilbene derivative that is found in some plants, fruits, seeds, and grape-derived products (such as red wine) and has been linked to a reduced risk of coronary disease and cancer. (67)

Phenotype: the characteristics of an organism as determined by both genetic makeup and environmental influences.

Phylogeny: the evolutionary development and history of a species or taxonomic group of species.

Pleiotropism is a central term in developmental genetics. In pleiotropism, a single gene affects a number of phenotypic traits in the same organism. These pleiotropic effects often seem to be unrelated to each other.

Polyphyodont: an animal that develops several sets of teeth successively throughout its life, as observed in many species.

Progeria: genetic disease resembling accelerated aging which typically affects children. Also called Hutchinson-Gilford syndrome.

Progeroid: a phenotype with features resembling accelerated aging.

Quiescent: in cell biology, a quiescent cell is one that is not dividing.

Rate of living theory: theory that argues that lifespan inversely correlates with metabolic rates.

Reactive oxygen species (ROS): any of a number of highly reactive forms of oxygen that are potential sources of damage; damage caused by ROS has been implicated in aging.

Replicative senescence: irreversible cessation of cell division of normally proliferating cells. It is also characterized by various biomarkers and can or not be accompanied by cell death.

Sirtuin: Any of a family of enzymes that occur in all living organisms and are thought to regulate cellular aging, apoptosis, and resistance to stress in more complex eukaryotic organisms. (71)

Stem cell: A stem cell is an undifferentiated cell of a multicellular organism which is capable of giving rise to indefinitely more cells of the same type, and from which certain other kinds of cell arise by differentiation. (72)

T lymphocyte: Type of lymphocyte that is produced or processed by the thymus gland and actively participating in the immune response. (73)

Senescence: the fundamental process of aging or aging itself. Can also refer to cellular aging in some contexts.

Senescent cell: normally dividing cell that is irreversibly growth arrested and exhibits a number of other biomarkers associated with cellular senescence.

Senolytic (from the words “senescence” and “lytic” — destroying) is among the class of small molecules under basic research to determine if they can selectively induce death of senescent cells. … The goal of those working to develop senolytic agents is to delay, prevent, alleviate, or reverse age-related diseases

Sensory gating describes neurological processes of filtering out redundant or unnecessary stimuli in the brain from all possible environmental stimuli. Also referred to as gating or filtering, sensory gating prevents an overload of irrelevant information in the higher cortical centers of the brain.

Soma: the entire body of an organism with the exception of the germ cells.

Stem cell: an undifferentiated cell that can divide, differentiate into specialized cells, and can self-renew to give rise to more stem cells.

Strategies for engineered negligible senescence (SENS): a proposal by Aubrey de Grey that details how by reversing seven forms of cellular and molecular age-related changes will allow us to cure aging.

Stress-induced premature senescence (SIPS): irreversible cell cycle arrest and associated cell phenotypes as the result of subcytotoxic stress.

Supercentenarian: someone 110 years of age or older.

Telomeres: the long end sequences of a DNA strand occurring at the tip of the chromosomes that play a key role in replicative senescence.

Telomerase: an enzyme that adds telomeric sequences to the telomeres and has been associated with cellular immortality.

Trait: a particular characteristic of an organism that can have different phenotypes.

Tomography: Method of producing a three-dimensional image of the internal structures of a solid object (such as the human body or the earth) by the observation and recording of the differences in the effects on the passage of waves of energy impinging on those structures. (76)

Tumorigenicity: The property of cells that describes their potential for forming tumors, or abnormal growth of cells. (77)

Tumor necrosis factor: A tumor necrosis factor is an inflammatory cytokine produced by macrophages/monocytes during acute inflammation and is responsible for a diverse range of signaling events within cells, leading to necrosis or apoptosis

Dr. Earl Ernest Guile is the author of The Singularity Prize. Guile is an epidemiologist who practices Tai Chi and has traveled to over sixty-two countries. https://amzn.to/2ALRk89

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Dr. Earl Ernest Guile is the author of The Singularity Prize. Guile is an epidemiologist who practices Tai Chi and has traveled to over sixty-two countries. https://amzn.to/2ALRk89

• Health
• Longevity
• Aging Research
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Earl Ernest Guile

Earl Ernest Guile is the author of The Singularity Prize. Guile is an epidemiologist who practices Tai Chi and has traveled to over sixty-two countries.