Biology of Aging new 1) (3)

Sinusitis and diabetes exhibit an initial increase in prevalence with age, followed by a decline in later years.

Asthma and kidney disease remain relatively low in prevalence across the entire age range.

Most clinicians believe that progeria is a form of segmental aging.

Aging is the process of becoming older, characterized by a gradual decline in physiological function and an increased risk of age-related diseases. Associated terminology includes senescence (the process of deterioration with age), longevity (the length of time an individual lives), and gerontology (the study of aging).

Signs and pathologies associated with aging include:

• Wrinkles and skin changes: Loss of elasticity and moisture.
• Decreased bone density: Increased risk of fractures.
• Cognitive decline: Memory loss and slower processing speed.
• Cardiovascular changes: Increased blood pressure and heart disease risk.
• Muscle atrophy: Loss of muscle mass and strength.

Research methods to investigate aging mechanisms include:

1. Longitudinal studies: Observing the same individuals over time to track changes.
2. Cross-sectional studies: Comparing different age groups at a single point in time.
3. Animal models: Using organisms like mice to study aging processes.
4. Cellular studies: Investigating cellular senescence and molecular changes in vitro.
5. Genetic studies: Exploring the role of genes in aging through genome-wide association studies (GWAS).

Poor sleep accelerates aging and increases the incidence of age-related diseases, including:

• Cognitive decline
• Alzheimer's disease
• Haematopoietic stem cell dysfunction
• Coronary heart disease

Improving the quantity and quality of sleep can be considered an anti-aging treatment that may:

• Prevent physical decline
• Slow down degeneration associated with aging
• Potentially reverse some aging effects

There is a significant association between better quality and quantity of sleep and increased plasma levels of S-Klotho, a gene family known as a senescence suppressor that is linked to prolonged life.

The initial stimuli that activate signaling pathways during exercise include:

• Mechanical loads
• Increased NAD+/NADH ratio
• Oxidative stress
• Reduced tissue oxygenation
• Increased ATP turnover
• Increased calcium flux

The signaling pathways activated by exercise include:

• mTOR: Leads to protein synthesis and hypertrophy.
• AKT: Involved in cell survival and growth.
• AMPK: Promotes mitochondrial biogenesis and autophagy.
• CaMKII: Contributes to calcium signaling and muscle contraction.

Downstream effects include:

• Mitochondrial biogenesis
• Fiber transformation
• Autophagy
• Cytoprotection
• Protein synthesis/degradation
• Hypertrophy
• Antioxidant defense

Oxidative stress acts as an initial stimulus that activates various signaling pathways during exercise, leading to adaptations in muscle tissue such as:

• Mitochondrial biogenesis
• Increased antioxidant defense
• Enhanced cytoprotection

The increased NAD+/NADH ratio during exercise activates signaling pathways that promote:

• Mitochondrial biogenesis
• Autophagy
• Enhanced energy metabolism
• Improved muscle function and adaptation

Mechanical loads during exercise activate signaling pathways that lead to:

• Protein synthesis
• Muscle hypertrophy
• Fiber transformation
• Enhanced cytoprotection and antioxidant defense

Aging leads to decreased neurogenesis, neurodegeneration, and cognitive alterations. Physical exercise positively impacts these areas by increasing neurogenesis, reducing neurodegeneration, and improving cognitive function.

Aging negatively impacts cardiovascular function by decreasing Qmax, increasing blood pressure, and reducing regional blood flow. Physical exercise enhances cardiovascular function by increasing Qmax, improving blood pressure, and enhancing regional blood flow and endothelial function.

Aging results in decreased muscle strength/power, endurance, and quality, along with reduced flexibility and motor performance. Exercise counteracts these effects by increasing muscle strength, endurance, and quality, and improving balance and mobility.

Interventions that can extend lifespan include:

• Caloric restriction: Reducing calorie intake without malnutrition can enhance longevity.
• Antioxidants: Compounds that neutralize free radicals may reduce oxidative stress.
• Exercise: Regular physical activity is associated with improved health and longevity.
• Hormesis: Mild stressors can promote adaptive responses that enhance resilience.
• Pharmacological agents: Drugs like rapamycin and metformin show potential in extending lifespan in model organisms.

13% of the population is currently over 65 years old.

The population of individuals over 65 years is expected to double in the next 25 years.

The population of individuals over 85 years old is projected to increase five-fold.

1 in 5 older adults are prescribed inappropriate medications.

Older adults account for half of physician time, half of prescription medications, and half of hospital stays.

The word 'senescence' is derived from the Latin word 'senex,' which means 'old man' or 'old age.'

The rate of aging has remained unchanged for thousands of years.

Life expectancy is different from aging rate and reflects many other factors beyond just the biological process of aging.

Aging is the gradual and spontaneous change that results in maturation through childhood and adolescence, followed by decline through middle and late age.

Senescence refers to the process by which the capacity for cell division, growth, and function is lost over time.

Life expectancy refers to the period of time in which the life events of a species typically occur.

Maximum lifespan (tmax) refers to the maximum period of time organisms of a given species can live, usually indicating the longest-lived individual.

Ageism is the stereotyping of habits and characteristics of older adults.

Life expectancy at birth is a measure of overall quality of life in a country and summarizes the mortality at all ages.

Macau has the highest life expectancy at birth with an average of 84.6 years.

Japan's life expectancy is 82.12 years, ranking 3rd in the world, while the United States has a life expectancy of 78.11 years, ranking 49th in the world.

The average life expectancy in Colorado in 2020 was 78.3 years.

Both heart disease and cancer show increasing prevalence with age, indicating a higher risk of these conditions as individuals grow older.

• Wrinkles on the face and body.
• Decreased acuity in sight, hearing, taste, and smell.
• Thinning and graying of hair.
• Weight gain, particularly around the waist and hips.
• Loss of bone density over time, especially in women.
• Slower reflexes and altered gait, leading to motor dysfunction.
• Decreased mental agility and declining memory.
• Complex diseases associated with aging arise from the interaction of genetic and environmental factors.

Aging individuals may experience:

• Neurodegeneration
• Dementia
• Parkinson disease
• Cerebral atrophy These changes are linked to abnormal compensatory mechanisms that predispose individuals to these conditions.

Age-related changes include:

• Changes in taste and smell
• Altered gut motility
• Intestinal microbiota abnormalities These factors can contribute to age-related anorexia and subsequent caloric and/or nutritional deficiency.

The weakening of smooth muscle can lead to:

• Development of diverticular disease
• Increased risk of bowel obstructions
• Higher likelihood of constipation

Decreased metabolic activity in the liver can lead to:

• Alterations in drug metabolism
• Reduced ability to detoxify substances, including medications

Aging leads to a reduced number of functional glomeruli and an increased prevalence of sclerotic changes within the glomeruli or renal vasculature.

There is a normal decrease in GFR observed in advanced age, which places the elderly at a much higher risk for complications if they develop chronic or acute kidney disease due to having less functional glomeruli as a result of normal aging physiology.

Aging lowers the threshold for cardiovascular disease development primarily due to a loss of cardioprotective and compensatory mechanisms. This includes vascular stiffening, increased left ventricular wall thickness, myocardial fibrosis, calcification of valves, decreased aerobic tolerance, and problematic cardiomyocyte remodeling, all of which increase the risks for cardiovascular diseases with aging.

Physiological changes associated with cardiovascular aging include:

1. Arterial stiffening
2. Increased left ventricular wall thickness
3. Myocardial fibrosis
4. Calcification of valves
5. Decreased aerobic tolerance
6. Increased problematic cardiomyocyte remodeling

These changes contribute to increased risks for cardiovascular diseases.

Arterial stiffening leads to several downstream effects:

• Increased pulse wave velocity
• Higher arterial systolic and pulse pressure
• Increased aortic root size and wall thickness

These changes can result in increased aortic impedance and left ventricular (LV) loading, affecting overall cardiac function and efficiency.

The primary age-related changes in the respiratory system include:

1. Loss of elasticity in lung tissues.
2. Decreased chest wall compliance, leading to increased work of breathing.
3. Increased residual volume and functional residual capacity.
4. Decreased strength and function of respiratory muscles.

These changes result in a lower threshold for compensating during acute illnesses or respiratory failure.

Aging leads to a decrease in the secretion of thyroxin and triiodothyronine, resulting in overall decreased metabolic activity, altered circadian rhythms, and increased susceptibility to reduced REM sleep.

With age, there are alterations in glucose metabolism and specifically in insulin secretion, which can promote the development of diabetes mellitus in the elderly.

Women typically experience menopause in their sixth decade of life, which is associated with an increased risk of cardiovascular disease, loss of bone mass, and atrophy of estrogen-responsive tissue.

Aging leads to impairment or alteration in specific sex-linked endocrine functions, affecting both men and women, with significant health implications.

The decrease in the proportion of individuals over 65 residing in nursing homes indicates an increase in Successful Aging, suggesting that more older adults are maintaining their independence and quality of life.

The percentage of persons aged 75-84 with disabilities has decreased to less than 30%, indicating improved health and functioning among this age group.

The key components associated with Successful Aging include:

1. Avoiding disease and disability
2. Social networks
3. Cognitive and physical health

The average lifespan is 87 years.

If you are not optimistic or able to let go of stress, you subtract five years from your lifespan estimate.

If you have family members who lived into their 90s, you add 10 years to your lifespan estimate.

If you do not exercise at least 30 minutes a day, three days a week, you subtract five years from your lifespan estimate.

If you regularly engage in challenging brain activities, you add five years to your lifespan estimate.

If you do not maintain a lean diet, you subtract seven years from your lifespan estimate.

If you smoke, you subtract five years from your lifespan estimate.

A common trait among all centenarians is optimism.

1. Increase early survival
2. Increase late survival
3. Delay senescence

Increased early or late survival affects mortality but does not impact the rate of aging.

• Short lifespan allows for quick experimental results.
• Easily maintained and inexpensive to keep.
• Less complex genetic and physiological systems compared to humans.

Genetically engineered animal models are crucial for exploring the basic mechanisms involved in aging, allowing researchers to manipulate specific genes and observe the effects on lifespan and health.

Artificial selection has resulted in an increase in mean lifespan from 40 days to 70 days for the selected population of fruit flies, compared to the unselected population.

The health span of fruit flies has increased from 30 days (blue band) to 60 days (pink band) due to artificial selection.

The two curves represent the survival rates of two populations of fruit flies: the selected population (black line with closed square markers) which has a longer lifespan, and the unselected population (black line with open circle markers) which has a shorter lifespan.

The shaded area above the horizontal dashed line at 90% indicates the proportion of fruit flies that survive above this threshold, highlighting the longevity of the selected population compared to the unselected population.

Key factors contributing to aging include:

Common aging-related diseases include:

The DNA damage theory posits that accumulated damage to DNA over time leads to cellular dysfunction and aging. This damage can result from environmental factors, metabolic processes, and errors during DNA replication.

Telomere shortening occurs as cells divide, leading to cellular senescence when telomeres become critically short. This process limits the number of times a cell can divide, contributing to aging and age-related diseases.

Mitochondrial dysfunction is characterized by a decline in mitochondrial function, leading to reduced energy production and increased oxidative stress. This dysfunction is associated with various age-related diseases and overall aging.

NAD metabolism is crucial for cellular energy production and maintaining cellular health. As NAD levels decline with age, it can affect various biological processes, including DNA repair and mitochondrial function, contributing to aging.

Other factors influencing aging include:

• Inflammation: Chronic inflammation can accelerate aging.
• Hormonal changes: Alterations in hormone levels can impact various bodily functions.
• Decline in protein folding chaperone network: This affects protein homeostasis and cellular function.
• Protein balance: Imbalances can lead to cellular stress and aging.

Exogenous sources of DNA damage include UV radiation, chemicals, X-rays, and chemotherapy.

Endogenous sources of DNA damage include reactive oxygen species (ROS), advanced glycation end products (AGEs), and aldehydes.

Genetic aberrations include mutations, deletions, aneuploidy, translocations, and dysfunctional telomeres.

Cellular consequences include cell death, senescence, stem-cell loss, and polyploidization.

Systemic consequences include various effects on the body that can lead to functional decline and disease.

Key components include aging, cell functional decline, atrophy, and inflammation.

DNA damage leads to cell and tissue pathology, which can result in various age-related diseases.

Telomere shortening occurs during cell division, leading to the accumulation of senescent cells. As telomeres shorten, they trigger cellular senescence, which is characterized by a halt in cell division and the secretion of pro-inflammatory factors.

Telomere dysfunction leads to DNA damage response (DDR), which induces the overexpression of cell cycle inhibitors like p53 and p21, accelerating cell senescence. Senescent cells secrete SASP factors that alter the extracellular matrix and recruit immune cells, promoting systemic chronic inflammation and related diseases.

Reactive oxygen species (ROS) induce damage to telomere sequences, leading to telomere shortening and decapitation. This damage triggers the DNA damage response (DDR), which accelerates cellular senescence.

Telomere shortening is associated with aging and contributes to the accumulation of senescent cells, which secrete inflammatory factors that can lead to systemic chronic inflammation and increase the risk of degenerative diseases.

Telomere length declines as age increases, with significant reductions observed from age 0 to age 65. Specifically, telomere length decreases from approximately 8,000 base pairs at age 0 to about 1,400 base pairs at age 65.

The key inducers of mitochondrial dysfunction in aging include:

1. Accumulation of mtDNA mutations
2. Release of damaged toxic mitochondrial material
3. Production of mitochondrial reactive oxygen species (mtROS)
4. Proteotoxicity
5. Deregulated metabolites (such as TCA intermediates and NAD+)

Mitochondrial dysfunction contributes to aging and age-related diseases through a series of effects:

• Oxidative stress
• Epigenetic alterations
• Proteotoxicity
• Proinflammatory response
• Cellular senescence
• Apoptosis

These processes lead to organismal decline and the development of age-related diseases.

1. Kynurenine pathway: Starts with Tryptophan converting to Quinolinic acid, then to NAD+.

2. Preiss-Handler pathway: Involves the conversion of Nicotinic Acid (NA) to NAD+ through intermediates like NAMN and NMN.

3. Salvage pathway: Recycles NAD+ from its breakdown products, involving enzymes such as Sirtuins and PARPs.

• Inflammageing: Chronic low-grade inflammation.
• Neurodegeneration: Impairment of neuronal function.
• Metabolic decline: Reduced metabolic efficiency.
• Genomic instability: Increased risk of DNA damage.
• Mitochondrial dysfunction: Impaired energy production.
• ROS accumulation: Increased oxidative stress.
• Loss of proteostasis: Disruption of protein homeostasis.

NAD+ metabolism is crucial for cellular functions and energy production. Decreased NAD+ levels contribute to:

• Aging: Impacts cellular repair and maintenance.
• Promoting senescence: Accelerates aging processes.
• Apoptosis and cancer: Alters cell survival pathways.

• Stress resistance genes
• Genes targeting inflammation
• Genes that slow basic metabolism, such as IGF
• Overall genetic stability

Altered gene expression due to quality control defects allows errors to accumulate as cells divide, leading to cells with diminished function.

The two forms of progeria in humans are Werner's syndrome (adult-onset progeria) and Hutchinson-Gilford syndrome (juvenile-onset progeria).

The mutation in Werner's syndrome codes for a DNA helicase, which is involved in DNA repair and unwinding.

• Chromosome instability syndromes
• Inability to repair DNA
• Increased rate of cancer
• Mutated helicase
• Inherited as autosomal recessive

• No helicase abnormality
• Uncertain pattern of inheritance
• Shorter than normal telomeres
• Early cell senescence

"Be OK with what you ultimately can't do, because there is so much you CAN do."

"Surround yourself with people you want to be around."

"Keep moving forward."

A 40% reduction in caloric intake results in healthier, long-lived rats, mice, monkeys, and shows early positive effects in humans. It alters biomarkers of aging, such as lower body temperature and reduced plasma insulin, and leads to more stable gene expression, indicating a delay in senescence.

Caloric restriction alters biomarkers of aging by resulting in:

1. Lower body temperature
2. Reduced plasma insulin

These changes are associated with healthier aging and longevity.

Caloric restriction leads to more stable gene expression, which is a sign of delayed senescence. This stability in gene expression is associated with healthier aging and longevity.

Aging typically leads to increased weight and regional adiposity, while decreasing fat-free mass. Physical exercise helps to decrease weight, increase fat-free mass, and enhance muscle mass and bone density.

Physical exercise enhances systemic antioxidant defense and DNA repair, countering genomic instability and multisystem pathology associated with aging.

Physical exercise prevents telomere shortening by increasing telomerase activity and TERT expression, which are crucial for maintaining telomere length and cellular health.

Exercise improves mitochondrial function and biogenesis by regulating factors such as PGC-1 and SIRT, which are essential for maintaining cellular energy metabolism and reducing mitochondrial dysfunction associated with aging.

Physical exercise exhibits anti-inflammatory effects by increasing levels of IL-4, IL-6, IL-10, and IL-13, which help combat the chronic inflammation often seen in aging.

1. Nutritional antioxidants: Incorporate foods and supplements rich in antioxidants.

2. Anti-inflammatory agents: Use medications like Minocycline and NSAIDs to reduce inflammation.

3. Cholesterol-lowering medications: Consider statins to manage cholesterol levels.

4. Mental health maintenance: Engage in self-care practices to improve mental health.

The average daily calorie intake in the US is 3,500 calories.

The normal daily calorie intake for an adult is 2,000 calories.

Moderate exercise can lower the risk of Alzheimer's disease by 50%.

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