Aging: Definitions, Theories, and Changes PDF

1 DEFINITIONS ❑ Geriatric medicine The branch of medicine specializing in the health and illnesses of old age and the appropriate care and services ❑ Gerontology Is the study of old age and of the process of becoming old. ❑ Senescence The process by which a cell looses its ability to...

1 DEFINITIONS ❑ Geriatric medicine The branch of medicine specializing in the health and illnesses of old age and the appropriate care and services ❑ Gerontology Is the study of old age and of the process of becoming old. ❑ Senescence The process by which a cell looses its ability to divide, grow, and function. This loss of function ultimately ends in death. A degenerative process, only. 2  Has no positive features Senility Refers to mental deterioration that often comes with old age, as in severe memory problems. If you find your shoes in the fridge, you may wonder if senility is occurring. TWO DIFFERENT AGES ❑ Chronological age refers to the actual time a human has been alive ❑ Biological age refers to how old that human seems o Most developed world countries have accepted the chronological age of 65 years as a definition of 'elderly' or older person CATEGORIES OF ELDERLY ❑ The "Young Old“ 65-74 y ❑ Old old 75-84 y ❑ Oldest old 85 and more PROGERIA ▪ known as Hutchinson-Gilford syndrome ▪ progressive genetic disorder that causes children to age rapidly, beginning in their first two years of life 3  ▪ During the first year, signs and symptoms, such as slow growth and hair loss, begin to appear. ▪ Heart problems or strokes are the eventual cause of death ▪ The average life expectancy for a child with progeria is about 13 years, There's no cure for progeria ▪ ongoing research shows some promise for treatment. PROGERIA FACTS ABOUT AGING The world population is rapidly ageing. Between 2000 and 2050, the proportion of the world's population over 60 years will double from about 11% to 22%. The absolute number of people aged 60 years and over is expected to increase from 605 million to 2 billion over the same period. 4 DIFFERENCES BETWEEN OLD AND YOUNG PEOPLE ❑ people are thus heterogeneous, and individual effects may be viewed as: Beneficial Neutral Disadvantageous LONGEVITY ❑ Longevity predictions are important : Decision making Initiating medications Performing procedures Screening tests 5 SUCCESSFUL AGING is used to identify older individuals who are Free from chronic disease Continue to function well into old age, both physically and cognitively. ESSENTIALLY HEALTHY Identifies those with No acute disease. No recent history of cancer. Normotensive. With well-controlled chronic disease. EXCEPTIONALLY HEALTHY Identifies older adults who Take no medications Have no chronic disease Are normotensive Have a normal body weight. GERIATRIC GIANTS In the 1960s, Bernard Isaacs described ‘Geriatric Giants’ : 1. incontinence 2. immobility 3. intellectual impairment 4. instability 6 5. iatrogenesis. THE 5MS OF GERIATRIC MEDICINE More recently, ‘5Ms’ have been proposed by Mary Tinnetti. 1. Mind : mentation, dementia, delirium, depression 2. Mobilization : impaired gait and balance, fall injury prevention 3. Medications : polypharmacy, optimal prescribing and deprescribing, adverse drug reactions 4. Multicomplexity : multimorbidity, complex bio-/psychosocial situations 5. Matters most : each individual’s own meaningful health outcome goals and care preferences THEORIES OF AGING Why do we age? How do we age? Biological theories of aging can be split into two types: I - Stochastic II- Programmed Stochastic theories suggest that damage to cellular components accumulates over time, leading to functional decline, and ultimately, death. Programmed theories propose that aging arises from a set biological timetable, possibly the same one that regulates childhood growth and development. 7 I - Stochastic Theories of Aging Free Radicals Mitochondrial Theory Genome Maintenance Theory Free Radicals Free radicals are just atoms or molecules with unpaired electrons. free radicals are highly reactive, and seek to steal an electron from other molecules to create a pair After the free radical finds a new electron, it leaves the molecule it stole from without a complete electron pair – a new free radical is born This chain reaction continues, leaving a path of molecular destruction in its wake, damaging important molecules like DNA and critical cellular proteins. ANTIOXIDANTS Antioxidants are molecules which can safely interact with free radicals and terminate the chain reaction before vital molecules are damaged. limiting or inhibiting the production of free radicals may reduce the rate of aging and the onset of age-related diseases 8 Mitochondrial Theory Mitochondria are cellular components that use glucose to generate the energy currency of the body known as ATP mitochondria are key sites for the production of superoxide radicals. The mitochondrial theory suggests that mitochondria produce large quantities of free radicals, which go on to damage the mitochondrial infrastructure, leading to an even less efficient process, and the production of more free radicals 9 Mitochondrial Theory Genome Maintenance Theory Radiation exposure led to DNA mutations, which accumulated over time, causing aging. This became known as somatic mutation theory. More broadly, somatic mutation theory is part of a broader class known as genome maintenance theories. These theories implicate DNA mutation, maintenance, and repair as crucial components of the aging process. II-Program Theories of Aging Telomere Shortening Theory Genetic Control Theory 10 Telomere Shortening Theory Telomeres, located at the ends of chromosomes, are highly specialized DNA sequences that serve as buffer regions, allowing the loss of DNA without the degradation of genetic information telomeres are like the protective plastic caps on the ends of your shoelaces The shortening of telomeres provides a mechanism to explain the presence of the Hayflick Limit. Telomeres shorten with successive cell divisions until they reach a critically short length, at which time they trigger permanent cell growth arrest. enzyme responsible for synthesizing telomeres – called telomerase 11 it has been hypothesized that increased telomerase expression may slow or reverse aging, 85% of human tumors have been found to express telomerase. Hayflick Limit The cells possessed some sort of “molecular clock” to keep track of how many times they had replicated. Cells had a way of recording how many cell divisions they had been through, and at some point, now termed the “hayflick limit”, stopped replicating. Genetic Control Theory Genetic control theory argues that the programmed upregulation and downregulation of certain genes controls the aging process a continuation of the genetic program that modulates growth and development earlier in life AGE-ASSOCIATED PHYSIOLOGIC CHANGES HEMATOPOIETIC SYSTEM Red cell life span, iron turnover, and blood volume are unchanged with age bone marrow mass decreases and fat in the bone marrow increases with increasing age Total circulating white cells counts do not change with age in healthy older people but the function of several cell types is reduced Greater propensity for clonal expansion with increasing age and this correlates with increased likelihood of development of hematologic malignancies Age is a significant risk factor for myelotoxicity due to chemotherapy regimens for malignancies 12  The number of platelets is unchanged with age, platelet responsiveness to a number of thrombotic stimulators is increased Old age should be considered a procoagulant state Age is an important risk factor for deep venous thrombosis. GASTROINTESTINAL TRACT ❑ Oropharynx The epithelial lining of the oral mucosa thins with age The gums recede, exposing the tooth cementum, which is more prone to decay, and predisposing older persons to root caries and incomplete mastication ❑ the salivary glands up to a 50 percent decrease in maximal saliva production from parotid salivary glands Up to 50 percent of older patients have subjective complaints of dry mouth increased resistance to flow across the upper esophageal sphincter Less effective mastication and decreased food clearance from the pharynx lead to increased aspiration risk in older adults. ❑ Esophagus Abnormal peristalsis after swallowing and non-peristaltic repetitive contractions, at one time attributed to old age and called “presbyesophagus” Decreased lower esophageal sphincter tone, results in increased gastric acid exposure 13 Presbyesophagus Abnormal esophageal motility in the elderly. irrespective of the kind of motility disorder. This includes: Diffuse esophageal spasm. Dilated esophagus with poor peristalsis ❑ Stomach Gastric acid production decreased dramatically with age, with a decrease in parietal cells and an increase in interstitial leukocytes Increased rates of gastritis and increased sensitivity to gastric irritants, such as non-steroidal anti-inflammatory medications or bisphosphonates ❑ Small intestine moderate villus atrophy calcium absorption from the gut lumen decreases because of decreased vitamin D receptors in the gut ❑ Large intestine Mucosal atrophy, cellular and structural abnormalities in the mucosal glands, hypertrophy of the muscularis mucosa, and atrophy of the muscularis externa Altered coordination of contraction and increased opioid sensitivity that may predispose the older person to drug-induced constipation Older women may be more predisposed to fecal incontinence than older men as the resting pressure and squeeze pressure decrease with age, resulting in decreased anal sphincter tone The risk of colon cancer increases with age 14 Hepatobiliary system Many liver functions decline, standard “liver function tests” (transaminases, alkaline phosphatase) are minimally affected by age Serum albumin declines slightly with normal human aging Metabolism of LDL cholesterol decreases with a reduction in LDL receptors in older patients , which could contribute to the higher serum LDL levels in older adults Cytochrome P450 content decreases with age this may account for the finding that metabolic clearance of many drugs is 20 to 40 percent slower in older people 15  The lower amounts of vitamin K antagonists needed to anticoagulate older people are consistent with age-related decreased synthesis of vitamin-K-dependent clotting factors regenerative response to liver injury declines with age older person more predisposed to cholesterol gallstone formation. THE RENAL SYSTEM Normal aging is associated with diffuse sclerosis of glomeruli Renal plasma blood flow is 40 percent lower in healthy normotensive older men than in young men Creatinine clearance decreases with age (7.5 to 10 ml per minute per decade) Fluid and electrolyte homeostasis are maintained relatively well with aging Reduction of urine acidification and impairment in excreting an acid load The older kidney is more prone to nephrotoxicity related to medications or intravenous contrast MUSCULOSKELETAL SYSTEM ❑ muscle mass Muscle mass decreases in relation to body weight Sarcopenia, age-related loss of muscle mass and strength, is defined as a decrease in appendicular muscle mass two standard deviations below the mean for young healthy adults Innervation of skeletal muscle decreases in men over 50 percent. 16 MUSCULOSKELETAL SYSTEM The recovery of older muscle after injury is slowed and frequently incomplete ❑ Bone increases the probability of fracture and the rate of repair is slowed, once fracture occurs CENTRAL NERVOUS SYSTEM The volume of the brain decreases about 7 cm3 per year after age 65, with greatest loss in the frontal and temporal lobes and greater loss of white matter than grey matter in cognitively normal older adults 17  Cerebral blood flow decreases heterogeneously by 5 to 20 percent Lipofuscin accumulates in certain areas of the brain, particularly the hippocampus and frontal cortex, but the impact of lipofuscin on function is unknown Neurofibrillary tangles and senile plaques occur in certain areas of the brain in normal aging, but to a lesser extent than in Alzheimer's disease. Attention span decreases with even simple attentive tasks Problem solving, reasoning about unfamiliar things, processing and learning new information, and attending to and manipulating one’s environment show a steady decline SKIN Atrophy Decreased elasticity Delayed wound healing Loss of hydration and decreased skin resilience 18  Sensory perception of the skin decreases, particularly in the lower extremities There is a decrease in subdermal fat. This loss of support contributes to the skin wrinkling and sagging, as well as to increased susceptibility to trauma. PHOTOAGING Is the result of chronic sun exposure and recurrent damage by the sun's ultraviolet light. Photoaging, not physiologic aging, produces most of the cosmetically undesirable changes in skin. The photoaged skin looks wrinkled, lax, yellowed, rough, and sometimes leathery. Photoaged skin has a higher tendency toward telangiectasias, and it is spottily hyperpigmented and hypopigmented. Photoaging changes are also partially reversible by topical treatment with retinoic acid. The photoaged skin looks wrinkled, lax, yellowed, rough, and sometimes leathery Photoaged skin has a higher tendency toward telangiectasias, and it is spottily hyperpigmented and hypopigmented 19 BODY TEMPERATURE Inability to maintain temperature. impaired sweating, and cutaneous vasoconstriction Impaired perception to low temperature. EYE ANATOMY SENSORY SYSTEM ❑ Eye Periorbital tissues atrophy; Eyelids become more relaxed. The lower lid flaccidity may lead to ectropion (eyelid turns outward) or entropion (eyelid turns inward). 20  Lacrimal gland function, tear production, and goblet cell function all decrease The conjunctiva atrophies and yellows. Deposition of cholesterol esters, cholesterol, and neutral fat in the cornea causes arcus senilis, an annular yellow-white deposit on the peripheral cornea ECTROPION ENTROPION ARCUS SENILIS 21  The retina becomes thinner because of a loss of neurons The iris becomes more rigid, yielding a smaller, more sluggishly responsive pupil The lens yellows, in part because of photo-oxidation in lens protein and an accumulation of insoluble protein. The yellowing of the lens causes decreased transmission of blue light Lens alterations increase light scattering, making the older person more sensitive to glare contrast sensitivity declines, so older persons need increased color contrast to discriminate between target and background PRESBYOPIA The distance needed to focus near objects increases because of decreased lens elasticity Presbyopia has gradual onset in the fourth decade with steady deterioration in static acuity (object at rest) and a more pronounced loss of dynamic visual acuity (ie, objects in motion). 22  ❑ Hearing Loss of hearing acuity, especially at higher frequencies (presbycusis) Difficulty with speech discrimination, and problems localizing the sources of sound Result in social isolation and increases risk for delirium during hospitalization Increasing the risk of cerumen impaction in older people ❑ Taste and smell the number of papillae on the tongue decreases with aging. Loss of taste in older patients is in large part due to decreased olfaction rather than taste itself. Decreased taste and smell sensation may result in decreased enjoyment of food and an age-related difficulty in sorting tastes of mixed or combined foods. IMMUNE SYSTEM Decrease in immune functions are among the most critical, contributing to the increased frequency of infections, malignancies, and autoimmune disorders. Immunosenescence, or the aging of the immune system Some of the responses that are most affected by age include 23  Decrease the ability of lymphocytes (both B and T cells) to work in concert to generate effective immune responses upon exposure to new antigens, in the form of either infections or vaccinations. An important concept in immunosenescence is that of loss of precise regulation of inflammatory processes. Older adults display cytokine profiles that are consistent with a chronic, low-level inflammatory state, which is sometimes referred to as “inflammaging” 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 ILOs 1. Describe the Conserved Process of Autophagy 2. Classify the different types of autophagy 3. Appraise the relationship between cellular Autophagy and Aging 4. Explain the link between ROS Generation, Autophagy and Aging 5. Identify Loss of Proteostasis in aging 6. Discuss Mitochondrial Dysfunction in aging 7. Recognize Nutrient Sensing Deregulation and the role of intermittent fasting 8. Review the Genomic related to autophagy and aging 9. Describe Telomere Attrition 10. Appraise Current and Future Autophagic Treatments in Aging and Age-Related Diseases 40  The Conserved Process of Autophagy Autophagy “Self – Eating” An intracellular catabolic pathway concerned with lysosomal degradation and turnover of cytoplasmic organelles and proteins. A highly conserved process that enables cells to degrade and recycle cytoplasmic components which are sequestered in double-membrane vesicles and degraded on fusion with the lysosome. It was first coined by Christian de Duve in 1963 to describe a process of lysosomal degradation of cytosolic components. In 2016, Nobel Prize was awarded to Yoshinori Ohsumi for discoveries of the mechanisms for autophagy after 27 years of research hoping it would have an impact upon human health. 41 Types of autophagy Selective and non-selective autophagy 42 Cellular Autophagy and Aging Overexpression of ATG5 in mice lead to enhancement of the autophagy process and anti-aging features, suggesting the importance of autophagy in the longevity of mice. In addition, these mice showed a better resistance to age-related obesity and enhanced insulin sensitivity, exhibiting an improved metabolism. Autophagy and Hallmarks of Aging ROS Generation In the most important work that links an overexpression of a single Atg gene with an increment in mammals' lifespan the authors 43 Mitophagy: Mitochondrial ROS, activate Atg4 , and this in turn leads to mitophagy activation in order to reduce the ROS levels by limiting the number of mitochondria per cell. Mitophagy activation upon cellular stress helps avoid detrimental effects of ROS Loss of Proteostasis Imbalance of proteostasis due to aging leads to protein aggregation, accumulation of misfolded proteins and in the end to cellular dysfunction. Autophagosomes and lysosomes decline in an age-dependent manner in muscles, heart, and several other tissues. Moreover, CMA has also been implicated in removing oxidized and potentially dangerous proteins by direct lysosomal degradation. 44 Mitochondrial Dysfunction in aging 45 age‐related decline mitochodrrial dysfunction >>> decline in autophagic capacity as a cause for accumulating altered molecules resulting from damaged and dead cells, which triggers inflammation response. Nutrient Sensing Deregulation and Intermittent Fasting The mammalian target of rapamycin (mTOR) kinase is the main negative regulator of autophagy and is exquisitely sensitive to dietary amino acids. When mTOR is activated, it shuts down autophagy. The main positive regulator is 5′ AMP-activated protein kinase (AMPK) which detects the AMP/ATP ratio and when this ratio is high signifying low cellular energy levels. When AMPK is activated, it activates autophagy. 46 Genomic Instability related to autophagy and aging 47  POSSIBLE ALTERATIONS THAT MAY CONTRIBUTE TO GENOMIC INSTABILITY IN AUTOPHAGY-DEFECTIVE CELLS: Failure to control the damage of checkpoint or repair proteins, Deregulated turnover of centrosomes, Insufficient energy for proper DNA replication and repair Excessive generation of reactive oxygen species due to inefficient removal of damaged mitochondria Telomere Attrition Repetitive sequences TTAGGG at the end of chromosomes. Telomerase is the special polymerase. Somatic cells of mammalian species lack the expression of telomerase. In each cell cycle, the telomere becomes shorter. This process is called telomere attrition. Aging leads to functional decline of telomerase in most of somatic cells. 48 Immortalized cells, such as germ cells and cancer cells, telomerase can sustain its activity. It is difficult to restore telomeres with the DNA repair machinery and this results in cellular senescence. In cells undergoing crisis, cells undergo cell death through autophagy activation, which is triggered by chromosome breakage. Current and Future Autophagic Treatments in Aging and Age- Related Diseases Induction or restoration of autophagy could alleviate aging symptoms. Three major anti-aging therapies evaluated over the last 30 years: - Autophagic inducers - Antioxidants - Caloric restriction AUTOPHAGY ACTIVATORS Rapamycin, an immunosuppressive macrolide, is a well-known autophagic activator via inhibition of mTOR. - Proved to increase lifespan - Rapamycin added during reperfusion after heart infarction in a myocardial ischemia mouse model improved the survival and cardiac functioning - Rapamycin improves whole metabolism. 49 Caloric restriction /Intermittent Fasting One of the most effective therapies in Reducing oxidative stress Prolonging lifespan 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156