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Unit XII: The Integrated Physiology

MBBS 1st Year - Complete Chapter Notes

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Chapter 102: Regulation of Body Temperature in Humans

Normal Body Temperature

• Core temperature (deep tissues): highly regulated, normally 97°F - 99.5°F (36°C - 37.5°C). This remains stable within ±0.6°C in health.
• Skin (shell) temperature: fluctuates freely with the environment, and is important for heat exchange.

Factors Affecting Body Temperature

1. Basal metabolic rate (BMR) of all cells
2. Muscle activity - exercise and shivering are major sources
3. Thyroid hormones (thyroxine) - increase cellular metabolism
4. Epinephrine/norepinephrine and sympathetic stimulation
5. Cell temperature - higher temperature accelerates chemical reactions
6. Thermogenic (specific dynamic) effect of food - digestion generates heat

Temperature Regulating Mechanisms

"When the rate of heat production in the body is greater than the rate at which heat is being lost, heat builds up in the body, and the body temperature rises. Conversely, when heat loss is greater than heat production, body temperature decreases." - Guyton & Hall

• The anterior hypothalamus is the body's thermoregulatory center (the "thermostat")
• It receives input from:
  • Peripheral thermoreceptors in the skin (warm & cold receptors)
  • Central thermoreceptors in the anterior hypothalamus itself monitoring blood/core temperature
• The hypothalamus compares sensed temperature against a set-point (~37°C) and activates corrective responses

• Shivering - rapid involuntary muscle contractions generate heat
• Vasoconstriction of skin blood vessels (sympathetic tone increase) - reduces heat loss from skin
• Increased metabolic rate via thyroid hormones
• Piloerection (goosebumps) - traps insulating air layer

• Sweating - evaporation is the most powerful heat loss mechanism
• Vasodilation of skin vessels (reduced sympathetic tone) - brings warm blood to skin surface for radiation, conduction, convection
• Increased respiration (minor effect in humans; major in panting animals)

Applied Aspects

• Defined as core temperature above normal due to resetting of the hypothalamic set-point upward by pyrogens
• Pyrogens (e.g., bacterial lipopolysaccharide endotoxins) stimulate macrophages to release cytokines, especially Interleukin-1 (IL-1), which is also called endogenous pyrogen
• IL-1 acts on the anterior hypothalamus to increase local prostaglandin synthesis, which raises the set-point
• The body then activates heat-generating mechanisms (shivering, vasoconstriction) until the new, higher set-point is reached - this is the "chills" phase
• Aspirin reduces fever by inhibiting cyclooxygenase (COX), blocking prostaglandin synthesis - this lowers the set-point back to normal, triggering heat-loss mechanisms (sweating, vasodilation) - Costanzo Physiology 7th Ed., p. (block2)

• Core temperature below 35°C
• At <32°C: loss of shivering (heat production fails), cardiac arrhythmias risk
• At <20°C: potentially fatal
• Causes: exposure to extreme cold, immersion in cold water, anesthesia

• Occurs when core temperature rises to levels causing tissue damage, due to failure of heat-dissipating mechanisms
• If sweating fails, heat cannot be released and temperature rises uncontrolled
• Medical emergency requiring rapid cooling

• A rare but life-threatening condition triggered by certain inhalation anesthetics in susceptible individuals
• Causes massive increase in skeletal muscle metabolic rate, extreme heat production that overwhelms dissipating mechanisms

• Frostnip - mild, reversible freezing of superficial skin
• Frostbite - ice crystal formation in tissues causing cell damage and vascular injury

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Chapter 103: Physiology of Exercise

Grading of Exercise

• Light exercise: <3 METs (e.g., slow walking)
• Moderate exercise: 3-6 METs (e.g., brisk walking, cycling)
• Vigorous/Hard exercise: >6 METs (e.g., running, sports)

• Type I (slow-twitch) fibers - recruited first, high oxidative capacity, fatigue-resistant - used for sustained activities
• Type IIa (fast-twitch oxidative) - intermediate
• Type IIx (fast-twitch glycolytic) - recruited last, powerful but fatigue quickly

"Physical exercise is often the greatest stress that the body encounters in the course of daily life... the body must make rapid, integrated adjustments at the level of cells and organ systems." - Medical Physiology (Boron & Boulpaep)

Cardio-respiratory Adaptation to Exercise

• Heart rate (HR) increases - due to withdrawal of vagal tone and increased sympathetic activity
• Stroke volume increases - due to increased venous return (Frank-Starling mechanism) and sympathetic stimulation of the heart
• Cardiac output (CO = HR × SV) can increase from 5 L/min at rest to 20-25 L/min during maximal exercise
• Blood pressure rises - systolic increases more than diastolic
• Vasodilation in active muscles (due to local metabolites: CO₂, H⁺, adenosine, K⁺) and vasoconstriction in visceral organs - blood is redirected to muscles

• Respiratory rate and tidal volume both increase
• Minute ventilation can rise from 5-6 L/min at rest to >100 L/min during maximal exercise
• Increased ventilation matches increased CO₂ production and O₂ demand
• Ventilatory threshold (anaerobic threshold): point at which lactic acid accumulates faster than it can be cleared; ventilation rises disproportionately to clear excess CO₂ from lactate buffering

Physiological Effects of Physical Training

• Musculoskeletal: increased muscle strength, bone density, joint flexibility
• Cardiovascular: lower resting HR, larger stroke volume, reduced cardiovascular disease risk
• Metabolic: improved insulin sensitivity, better glucose and lipid metabolism, increased fat oxidation
• Respiratory: improved efficiency, larger vital capacity
• Psychological: reduced anxiety and depression, improved mood (endorphin release)

Exercise under Heat and Cold

• Competing demands between muscles (needing blood flow) and skin (needing blood flow for cooling) create cardiovascular strain
• Core temperature rises faster; risk of heat exhaustion and heat stroke
• Fluid replacement (hydration) and acclimatization are essential
• Acclimatization over 7-14 days increases plasma volume, improves sweating efficiency and earlier onset of sweating

• Shivering increases heat production
• Vasoconstriction protects core temperature but peripheral extremities are at risk of cold injury
• Wet cold and wind greatly increase heat loss

Consequences of Sedentary Lifestyle

• Cardiovascular disease: sedentary lifestyle is associated with increased inflammation, insulin resistance, decreased wall shear stress, and heightened vascular disease risk
• Obesity and metabolic syndrome: reduced caloric expenditure, impaired glucose metabolism
• Osteoporosis: reduced mechanical loading leads to bone loss
• Muscle atrophy (disuse atrophy)
• Depression and anxiety
• Increased all-cause mortality

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Chapter 104: Physiology of Yoga

General Introduction

Types of Yogic Exercises

• Relaxative (e.g., Shavasana)
• Meditative (e.g., Padmasana)
• Cultural/corrective - for posture and organ function

Health Benefits of Yoga Practice

• Reduces resting heart rate and blood pressure
• Improves heart rate variability (reflects improved parasympathetic tone)
• Lowers cholesterol and triglycerides

• Pranayama improves lung volumes - vital capacity (VC) and tidal volume increase
• Improves respiratory muscle strength and efficiency

• Increases flexibility and range of joint motion
• Strengthens postural muscles and core stability
• Helps prevent and manage low back pain

• Reduces cortisol (stress hormone) levels
• Improves insulin sensitivity; beneficial in Type 2 diabetes
• Balances thyroid function

• Stimulates parasympathetic nervous system (rest-and-digest), countering chronic sympathetic over-activation
• Reduces anxiety, depression, and perceived stress
• Improves sleep quality
• Increases GABA levels in the brain (anti-anxiety)

Yoga in Health and Disease

• Hypertension: yoga's parasympathomimetic effect reduces sympathetic drive and lowers BP
• Diabetes mellitus: improves glycemic control and insulin sensitivity
• Asthma and COPD: pranayama improves breathing efficiency
• Depression/anxiety: meditative practices reduce cortisol, increase serotonin
• Obesity: combined effect of physical activity + stress reduction + improved eating behaviors
• Osteoporosis: weight-bearing asanas stimulate bone formation
• Arthritis: gentle movement improves joint lubrication and reduces stiffness

Yoga vs. Conventional Exercises

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Chapter 105: Physiology of Infancy and Aging

Physiology of Infancy

• Circulatory transition: The foramen ovale and ductus arteriosus close (functional closure within hours, anatomical within weeks), converting from parallel fetal circulation to adult serial circulation
• Respiratory onset: First breath is triggered by hypoxia, hypercarbia, cold stimulation, and tactile stimulation at birth
• Thermoregulation: Neonates are poikilothermic - they lose heat rapidly due to high surface area:body mass ratio and thin subcutaneous fat. Brown adipose tissue (BAT) - unique to neonates - provides non-shivering thermogenesis via uncoupling of oxidative phosphorylation

Aging and Free Radicals and Antioxidants

• Normal byproduct of mitochondrial oxidative phosphorylation (electron leakage)
• Inflammatory reactions
• UV radiation, ionizing radiation
• Environmental toxins, cigarette smoke
• Ischemia-reperfusion injury

• DNA damage: strand breaks, base modifications - leads to mutations and cancer
• Lipid peroxidation: damage to cell membranes
• Protein oxidation: inactivates enzymes
• Mitochondrial damage: creates a vicious cycle of more ROS production

• Cardiovascular: Reduced cardiac output, arterial stiffening (atherosclerosis), hypertension
• Respiratory: Reduced vital capacity, decreased elastic recoil of lungs
• Renal: Reduced GFR (decreases ~1% per year after age 40), reduced tubular function
• Nervous system: Neuronal loss, reduced neurotransmitter levels, slowed conduction velocities, memory decline
• Musculoskeletal: Sarcopenia (muscle wasting), osteoporosis, joint degeneration
• Immune system: Immunosenescence - reduced T-cell function, increased autoimmunity and infection susceptibility
• Hormonal: Menopause (women), andropause (men), reduced growth hormone and IGF-1

Brain Death

1. Coma - completely unresponsive to all external stimuli
2. Absence of all brainstem reflexes:
   • No pupillary light reflex (pupils fixed and dilated)
   • No corneal reflex
   • No oculovestibular (caloric) reflex
   • No gag or cough reflex
   • No oculocephalic reflex (doll's eye absent)
3. Apnea test positive - no spontaneous breathing even when PaCO₂ rises to ≥60 mmHg, confirming complete loss of respiratory drive
4. Irreversibility confirmed - known cause, reversible causes ruled out (hypothermia, drug intoxication, metabolic disturbances excluded)

• EEG - shows electrocerebral silence (flat trace)
• Cerebral angiography - no intracranial blood flow
• Transcranial Doppler - absent cerebral blood flow
• Radionuclide scan (SPECT) - no cerebral perfusion

• In PVS, the brainstem functions are preserved (breathing, reflexes intact), but higher cortical functions are lost
• Brain death is complete and irreversible loss including brainstem - PVS is not brain death

• Brain death declaration allows discontinuation of mechanical ventilation
• It is the medical and legal prerequisite for organ donation
• Two independent physicians must certify brain death

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Quick Revision Summary for Exams

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Summary:

• 5 out of 7 topics are fully or substantially covered.
• Role of Sleep is not covered at all - it is not part of the Unit XII chapters shown in your image.
• Oxidative stress is covered by another name (free radical damage/ROS) - the concepts are identical, just the terminology differs.

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UNIT XII - INTEGRATED PHYSIOLOGY

7 Topic Master Notes | MBBS 1st Year University Exam

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TOPIC 1: THERMOREGULATION

Definition: Thermoregulation is the ability of the body to maintain its core temperature within a narrow normal range (36-37.5°C) despite wide variations in environmental temperature.

Normal Body Temperature

• Core temperature (rectal/esophageal): 37°C (98.6°F) - most accurate
• Oral temperature: ~0.5°C lower than rectal
• Axillary temperature: ~1°C lower than rectal
• Diurnal variation: Lowest at 4-6 AM, highest at 6-8 PM (up to 0.5°C difference)
• Temperature rises with exercise, emotions, menstrual cycle (rises at ovulation)

The Hypothalamic Thermostat (Master Controller)

THERMORECEPTORS ──────────────────────────────────────────────────────────►
                 ↗ Peripheral receptors (warm/cold receptors in skin)        ANTERIOR
                 ↘ Central receptors (in anterior hypothalamus itself)   ──► HYPOTHALAMUS
                                                                              (Set-point ~37°C)
                                                                                  ↓
                                          ┌─────────────────────────────────────┤
                                          ↓                                     ↓
                          TEMP BELOW SET-POINT                     TEMP ABOVE SET-POINT
                          (Heat Conservation)                       (Heat Dissipation)

• Shivering (rapid involuntary muscle contractions)
• Vasoconstriction of skin vessels (less blood to skin)
• Piloerection (goosebumps - trap insulating air)
• Increased thyroid hormone secretion (raises BMR)
• Behavioral: seeking warmth, curling up

• Sweating (main mechanism in humans)
• Vasodilation of skin vessels (more blood to skin)
• Inhibition of shivering
• Behavioral: seeking shade, removing clothes

"The temperature-regulating center in the anterior hypothalamus receives information about environmental temperature from thermoreceptors in the skin and about core temperature from thermoreceptors in the anterior hypothalamus itself. The anterior hypothalamus then orchestrates the appropriate responses." - Costanzo Physiology

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TOPIC 2: MECHANISMS OF HEAT GAIN AND HEAT LOSS

A. MECHANISMS OF HEAT GAIN (Heat Production)

• Especially important in neonates
• Contains uncoupling protein-1 (thermogenin) in mitochondria
• Instead of making ATP, energy is released directly as heat
• Stimulated by noradrenaline

B. MECHANISMS OF HEAT LOSS

1. Core → Skin (via blood flow)
2. Skin → Environment (via physical processes)

Stage 1: Core to Skin - Blood as Heat Carrier

• Skin has a rich venous plexus supplied by capillaries and arteriovenous anastomoses (especially in hands, feet, ears)
• Skin blood flow can range from near-zero to 30% of total cardiac output
• Vasodilation = high skin flow = efficient heat transfer to skin surface
• Vasoconstriction = low skin flow = body retains heat

Stage 2: Skin to Environment - The 4 Physical Methods

• Skin + subcutaneous tissue + fat act as natural insulation
• Fat conducts heat only 1/3 as readily as other tissues
• This is why insulation is better in women (more subcutaneous fat)

"The rate at which heat is lost is determined almost entirely by two factors: (1) how rapidly heat can be conducted from where it is produced in the body core to the skin, and (2) how rapidly heat can then be transferred from the skin to the surroundings." - Guyton & Hall

Sweating - Key Details (Exam Favourite)

• Sweat glands innervated by cholinergic sympathetic fibers (unusual - sympathetic but ACh-secreting)
• Hypothalamus → spinal cord → sympathetic outflow → sweat glands
• Precursor secretion is like plasma (Na⁺ 142 mEq/L) but protein-free
• As sweat passes through the duct, Na⁺ and Cl⁻ are reabsorbed
• Acclimatization to heat improves aldosterone-mediated Na⁺ reabsorption → sweat becomes more dilute

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TOPIC 3: ROLE OF SLEEP

Definition: Sleep is a state of unconsciousness from which a person can be aroused by sensory or other stimuli - this distinguishes it from coma (from which one cannot be aroused). - Guyton & Hall

Types of Sleep - Two Major Types

1. NREM Sleep (Non-Rapid Eye Movement = Slow-Wave Sleep)

• Makes up ~75% of total sleep time
• Deep, restful sleep
• Associated with decreased heart rate, BP, respiratory rate, metabolic rate
• EEG shows slow, high-voltage waves (delta waves) in deep stages
• Occurs predominantly in the first half of the night
• 4 stages (Stage 1 → lightest; Stage 4 → deepest)

2. REM Sleep (Rapid Eye Movement = Paradoxical Sleep)

• Makes up ~25% of total sleep time
• Occurs in episodes every 90 minutes, each lasting 5-30 minutes
• REM periods get longer as the night progresses

1. Rapid, conjugate eye movements (EOM active)
2. Vivid dreaming occurs
3. EEG resembles wakefulness (beta waves - desynchronized) - "paradoxical"
4. Peripheral muscle atonia - spinal muscle inhibition (body is paralyzed)
5. Heart rate and respiratory rate are irregular
6. Brain metabolism may increase by 20%
7. Person is more difficult to arouse than in deep NREM, yet wakes spontaneously in morning during REM

"REM sleep is also called paradoxical sleep because it is a paradox that a person can still be asleep despite the presence of marked activity in the brain." - Guyton & Hall

Neuroscience of Sleep: Brain Waves (EEG Patterns)

Functions of Sleep (Physiological Role)

1. Neural restoration - restores balance among neuronal centers
2. Memory consolidation - facilitates learning; synaptic strengthening
3. Synaptic pruning - erases unimportant information ("synaptic homeostasis theory")
4. Metabolic waste clearance - the glymphatic system in the brain is most active during sleep, clearing metabolic waste products (including beta-amyloid)
5. Hormonal regulation:
   • Growth hormone (GH) - peak release during deep NREM (Stage 4) sleep
   • Cortisol - rises in early morning hours (pre-waking)
   • Prolactin - rises during sleep
   • Melatonin - signals sleep onset (from pineal gland, in darkness)
6. Immune function - cytokine release during sleep enhances immune response; sickness promotes sleep to divert energy to healing
7. Cardiovascular rest - HR and BP drop during NREM, reducing cardiac workload
8. Energy conservation

Effects of Sleep Deprivation

• Impaired cognition, concentration, and memory
• Irritability, mood disturbances; psychosis with prolonged deprivation
• Increased cortisol (chronic stress response)
• Impaired glucose tolerance (increased diabetes risk)
• Increased risk of hypertension and cardiovascular disease
• Immunosuppression
• Increased leptin resistance (obesity risk)

"Sleep deprivation affects the functions of the central nervous system. Prolonged wakefulness is often associated with progressive malfunction of the thought processes and sometimes even causes abnormal behavioral activities." - Guyton & Hall

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TOPIC 4: CONSEQUENCES OF SEDENTARY LIFESTYLE

Definition: A sedentary lifestyle is one with little or no physical activity, typically <150 minutes of moderate-intensity activity per week.

Cardiovascular Consequences

• Decreased wall shear stress on arterial walls → endothelial dysfunction
• Increased inflammatory mediators → accelerates atherosclerosis
• Insulin resistance → metabolic syndrome
• Hypertension - reduced cardiovascular fitness
• Increased risk of coronary artery disease, heart failure, stroke
• Physical inactivity is now the 4th leading risk factor for global mortality (WHO)

Metabolic Consequences

• Obesity - reduced caloric expenditure with unchanged/increased intake
• Type 2 Diabetes Mellitus - impaired glucose uptake by muscles, insulin resistance
• Dyslipidemia - elevated LDL, triglycerides; reduced HDL
• Non-alcoholic fatty liver disease (NAFLD)

Musculoskeletal Consequences

• Sarcopenia - progressive loss of skeletal muscle mass and strength
• Osteoporosis - reduced mechanical loading = reduced osteoblast stimulation = bone loss
• Joint stiffness - reduced synovial fluid production and cartilage nutrition
• Low back pain - weak postural and core muscles

Respiratory Consequences

• Reduced vital capacity and lung compliance
• Decreased respiratory muscle endurance

Neurological/Psychological Consequences

• Depression and anxiety - reduced endorphin and serotonin release
• Cognitive decline - reduced neuroplasticity and BDNF (Brain-Derived Neurotrophic Factor)
• Poor sleep quality

Cancer Risk

• Sedentary behavior is associated with increased risk of colon, breast, and endometrial cancers (chronic inflammation, insulin, and estrogen as mediators)

Summary Table - Key Numbers to Remember

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TOPIC 5: OXIDATIVE STRESS

Definition: Oxidative stress refers to cellular damage induced by the accumulation of Reactive Oxygen Species (ROS) - a form of free radical - when production overwhelms the body's antioxidant defense capacity. - Robbins Basic Pathology

What are Free Radicals / ROS?

• Chemical species with a single unpaired electron in an outer orbital
• Extremely unstable - readily react with DNA, proteins, and lipids
• Can convert attacked molecules into free radicals themselves, creating a chain reaction

Sources of ROS (How They Are Generated)

• O₂ is reduced by sequential addition of 4 electrons → H₂O
• This process is imperfect; partially reduced oxygen creates:
  • Superoxide (O₂•⁻)
  • Hydrogen peroxide (H₂O₂)
  • Hydroxyl radical (•OH) - most reactive; formed from H₂O₂ + Fe²⁺ (Fenton reaction)

• Neutrophils and macrophages use respiratory burst (oxidative burst) to kill microbes
• Phagocyte oxidase → Superoxide → H₂O₂ → Hypochlorite (ClO⁻) via myeloperoxidase
• ROS released from neutrophils can injure surrounding tissues

• Ionizing radiation (X-rays, UV light)
• Cigarette smoke
• Environmental pollutants
• Certain drugs and toxins

Principal Free Radicals - Summary Table

Cellular Damage Caused by ROS

1. Lipid peroxidation - ROS attack double bonds in membrane phospholipids → autocatalytic chain reaction → destroys plasma, mitochondrial, and lysosomal membranes
2. Protein crosslinking and oxidation - free radicals promote sulfhydryl-mediated crosslinking → enzyme inactivation, structural protein damage
3. DNA damage - single and double-strand breaks, base modifications → mutations, impaired transcription, cancer, accelerated aging
4. Mitochondrial damage - damaged mitochondria produce even more ROS (vicious cycle)

"Free radicals are chemical species with a single unpaired electron in an outer orbital. Such chemical species are extremely unstable and readily react with inorganic and organic compounds, such as nucleic acids, proteins, and lipids." - Robbins Basic Pathology

Conditions Where Oxidative Stress is Prominent

• Aging (central mechanism)
• Atherosclerosis
• Ischemia-reperfusion injury (e.g., after heart attack)
• Cancer
• Diabetes mellitus
• Neurodegenerative diseases (Alzheimer's, Parkinson's)
• Chronic inflammatory diseases
• Chemical and radiation injury

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TOPIC 6: ROLE OF ANTIOXIDANTS

Definition: Antioxidants are substances that inhibit or delay oxidative damage by neutralizing free radicals or preventing their formation.

The Body's Antioxidant Defense Systems

A. Enzymatic Antioxidants (Endogenous - made by the body)

O₂•⁻ ──(SOD)──→ H₂O₂ ──(Catalase / GSH Peroxidase)──→ H₂O + O₂ (harmless)

B. Non-Enzymatic Antioxidants (Dietary/Exogenous)

Antioxidants and Disease Prevention

• Cardiovascular disease - Vitamins C and E reduce LDL oxidation (key step in atherosclerosis)
• Cancer - antioxidants reduce DNA damage from ROS
• Aging - slowing of free radical accumulation → slower cellular damage
• Neurodegenerative disease - protect neurons from oxidative damage
• Diabetes - reduce oxidative damage to pancreatic beta cells and vascular endothelium

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TOPIC 7: AGING - PHYSIOLOGY

Definition: Aging (senescence) is the progressive, time-dependent deterioration of physiological functions that increases susceptibility to disease and leads to death. It is a universal, irreversible, and intrinsic process.

Theories of Aging

Free Radical Theory (Most Important for Exams)

Normal metabolism
       ↓
  Mitochondrial ROS production (O₂•⁻, H₂O₂, •OH)
       ↓
  Overwhelms antioxidant defenses with age
       ↓
  Accumulation of:
  - DNA mutations (nuclear + mitochondrial)
  - Lipid peroxide damage to membranes
  - Protein crosslinking and inactivation
       ↓
  Cellular dysfunction → tissue degeneration → organ failure → AGING
       ↑
  Damaged mitochondria produce MORE ROS (vicious cycle)

Age-Related Changes in Body Systems

Aging of the Nervous System - Key Points

• Gradual neuronal loss (brain weight decreases by ~10% between ages 20-90)
• ↓ Dopamine, acetylcholine, serotonin levels
• ↓ Speed of nerve conduction → slower reflexes
• ↓ Short-term memory (hippocampal changes)
• Increased risk of Alzheimer's disease (amyloid-beta accumulation)

Factors That Accelerate Aging

• Chronic oxidative stress (smoking, pollution, poor diet)
• Chronic inflammation ("inflammaging")
• Sedentary lifestyle
• Poor sleep
• Psychological stress (↑ cortisol → immune suppression, telomere shortening)

Factors That Slow Aging (Clinically Relevant)

• Caloric restriction - reduces ROS production from mitochondria (best studied anti-aging intervention in animals)
• Regular exercise - upregulates antioxidant enzymes, preserves muscle mass, improves mitochondrial function
• Antioxidant-rich diet - Vitamins C, E, β-carotene, polyphenols
• Quality sleep - glymphatic clearance of brain waste
• Social engagement - cognitive stimulation, reduced cortisol

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EXAM QUICK REVISION - ONE-LINERS