Aging Physiology: Age-Related Changes Across Body Systems and Theories of Aging

Introduction

Aging is characterized by progressive loss of physiological function, reduced reserve capacity (homeostenosis), and increased vulnerability to disease and stress. The rate of aging varies between individuals and is influenced by genetics, environment, and lifestyle. Understanding age-related changes is essential for distinguishing normal aging from disease.

Theories of Aging

Major Theories

Theory	Mechanism	Evidence
Telomere shortening	Each cell division shortens telomeres; critically short telomeres trigger senescence or apoptosis	Strong; telomere length correlates with lifespan; telomerase extends lifespan in animal models
Free radical/oxidative stress	Accumulation of reactive oxygen species (ROS) damages DNA, proteins, and lipids	Moderate; antioxidants extend lifespan in some models but not humans
Mitochondrial theory	Accumulated mtDNA mutations impair oxidative phosphorylation, increasing ROS production	Moderate; mtDNA mutation load increases with age
Caloric restriction	Reduced caloric intake activates sirtuins, AMPK, mTOR inhibition, and autophagy	Strong in model organisms; moderate in primates; human epidemiology supports
Epigenetic clock	Age-related changes in DNA methylation patterns (Horvath clock) predict biological age	Strong correlation; epigenetic age may be modifiable
Inflammaging	Chronic low-grade inflammation (IL-6, TNF-alpha, CRP) increases with age and drives age-related disease	Strong; inflammation predicts frailty, CVD, dementia
Immunosenescence	Age-related decline in immune function increases infection risk and decreases vaccine response	Strong
Growth hormone/IGF-1 axis	Reduced GH/IGF-1 signaling extends lifespan in many species	Complex; low IGF-1 associated with longevity but also frailty

Cardiovascular System

Parameter	Age-Related Change	Clinical Impact
Arterial stiffness	Increased (decreased compliance from elastin fragmentation, collagen cross-linking, calcification)	Increased systolic BP, widened pulse pressure, increased LV afterload
Left ventricular wall thickness	Increased (mild concentric hypertrophy)	Reduced early diastolic filling (diastolic dysfunction)
Maximum heart rate	Decreased (maximum HR = 220 - age)	Reduced maximum cardiac output
Baroreceptor sensitivity	Decreased	Increased orthostatic hypotension, postprandial hypotension
Conduction system fibrosis	Increased fibrosis of SA node, AV node, bundle branches	Increased risk of arrhythmias (AFib, sick sinus syndrome, heart block)
Aortic valve	Thickening, calcification	Aortic sclerosis (25% >65); aortic stenosis (2-7% >75)
Endothelial function	Impaired nitric oxide-mediated vasodilation	Increased vascular resistance, decreased perfusion
Cardiac output (rest)	No significant change	Normal resting function
Cardiac output (maximum)	Decreased 20-30% by age 65	Reduced exercise capacity

Respiratory System

Parameter	Age-Related Change	Clinical Impact
Chest wall compliance	Decreased (stiffer rib cage, calcified costal cartilages)	Increased work of breathing
Lung elastic recoil	Decreased (loss of elastin)	Increased closing volume, air trapping
FEV1	Decreases 20-30 mL/year after age 25	Reduced expiratory flow rates
FVC	Decreases 15-30 mL/year	Reduced total volume
FEV1/FVC ratio	Decreases slightly (maintain >0.70)	May approach obstructive pattern
DLCO (diffusing capacity)	Decreases 0.5-1% per year	Reduced gas exchange efficiency
Arterial PaO2	Decreases (mild)	Lower baseline oxygen
Ventilatory response to hypoxia/hypercapnia	Decreased	Blunted response to respiratory stress
Mucus clearance	Impaired (reduced ciliary function)	Increased infection risk
Respiratory muscle strength	Decreased (diaphragm, intercostals)	Reduced cough effectiveness

Renal System

Parameter	Age-Related Change	Clinical Impact
Glomerular filtration rate (GFR)	Declines approximately 1 mL/min/year after age 30-40	Reduced drug clearance; note: serum Cr may stay normal due to reduced muscle mass
Renal blood flow	Decreases 10% per decade	Reduced perfusion reserve
Number of glomeruli	Decreases 30-50% by age 70	Reduced filtration reserve
Tubular function	Impaired concentrating and diluting ability	Reduced response to fluid/electrolyte stress
Urinary concentrating ability	Decreased maximum urine osmolality	Predisposition to dehydration
Sodium conservation	Impaired	Predisposition to hyponatremia or volume depletion
Potassium handling	Impaired (especially with RAAS-altering medications)	Increased hyperkalemia risk
Nocturnal natriuresis	Loss of day-night difference	Nocturia
Bladder capacity	Decreased, with increased residual volume	Urinary frequency, incomplete emptying

Immune System (Immunosenescence)

Component	Change	Clinical Impact
T-cell production (thymic involution)	Markedly reduced	Decreased naive T cells, increased memory T cells
T-cell function	Reduced proliferation, impaired signaling	Poor response to new antigens, vaccines
B-cell production	Decreased	Reduced antibody diversity
Antibody response	Decreased affinity, specificity	Poor vaccine response (influenza, pneumococcal, tetanus)
Innate immunity (neutrophils, macrophages)	Reduced phagocytic function, chemotaxis	Slower wound healing
Natural killer cells	Increased number but decreased function	Reduced tumor surveillance
Cytokine production	Increased pro-inflammatory cytokines (IL-6, TNF-alpha, CRP)	Chronic inflammation (inflammaging) contributes to frailty
Memory T/B cells	Maintained	Protection against previously encountered pathogens retained

Musculoskeletal System

Parameter	Age-Related Change	Clinical Impact
Bone mineral density	Decreases (accelerates in women after menopause, men after 70)	Osteoporosis, fracture risk
Muscle mass (sarcopenia)	Losses of 3-8% per decade after age 30; accelerates after 60	Weakness, frailty, falls, reduced mobility
Muscle strength	Decreases 10-15% per decade after age 50	Functional decline, difficulty with ADLs
Type II (fast-twitch) muscle fibers	Selective atrophy	Reduced power, speed, balance
Cartilage	Thinning, fibrillation, decreased water content	Osteoarthritis
Intervertebral discs	Desiccation, herniation	Height loss (1-3 inches total), kyphosis
Tendon/ligament strength	Decreased	Increased injury risk
Joint range of motion	Decreased	Stiffness, functional limitation

Nervous System

Parameter	Age-Related Change	Clinical Impact
Brain weight	Decreases 5-10%	Mild atrophy (frontal, temporal, hippocampus)
Cortical thinning	Especially prefrontal cortex	Processing speed decline
White matter	Loss of myelinated fibers; white matter hyperintensities	Cognitive slowing, executive function decline
Neurotransmitters	Reduced dopamine, serotonin, acetylcholine	Mood changes, motor slowing, memory changes
Cerebral blood flow	Decreased 15-20%	Reduced metabolic reserve
Sleep architecture	Decreased N3 slow wave sleep, increased awakenings	Lighter, more fragmented sleep
Reaction time	Increased	Slower responses
Processing speed	Decreased	Cognitive tasks take longer
Memory	Episodic memory declines; semantic memory preserved	Forgetting names, word-finding difficulty (“tip of the tongue”)
Executive function	Decline in complex attention, task-switching, inhibition	Difficulty multitasking, decision-making slowing

Sensory Systems

System	Age-Related Change	Clinical Impact
Vision	Presbyopia (loss of accommodation) requiring reading glasses by 40-50	Difficulty with near tasks
Vision (lens)	Cataract formation (lens opacification); 50% have cataracts by age 65	Reduced visual acuity, glare sensitivity
Vision (macula)	Age-related macular degeneration (AMD)	Central vision loss
Vision (intraocular pressure)	Increased risk of glaucoma	Peripheral vision loss
Pupil size	Decreased (senile miosis)	Reduced night vision, slow dark adaptation
Hearing	Presbycusis (high-frequency hearing loss); 1/3 affected by 65, 1/2 by 75	Difficulty hearing in background noise, social isolation
Taste	Decreased number of taste buds; threshold increased >50%	Reduced taste perception, may over-salt/over-sugar food
Smell	Reduced olfactory sensitivity; 50% >65 have significant loss	Reduced appetite, decreased ability to detect gas leaks or spoiled food
Touch/vibration	Decreased vibratory sense (especially in feet)	Reduced proprioception, fall risk
Pain perception	May be altered (increased threshold for some pain)	Atypical presentation of disease (e.g., “silent” MI)

Endocrine System

Parameter	Age-Related Change	Clinical Impact
Growth hormone	Decreased 15% per decade	Reduced muscle mass, increased fat
IGF-1	Decreased in parallel with GH	Similar to GH
Testosterone (men)	Decreases 1% per year after 30	20% of men >70 have low testosterone
Estrogen (women)	Marked drop at menopause	Menopausal symptoms, bone loss, CV risk
Thyroid function	TSH increases slightly; T3 decreases	Mild hypothyroidism common
Parathyroid hormone	Increases with age	Secondary hyperparathyroidism, bone loss
Vitamin D	Decreased absorption, synthesis	Deficiency in 30-50% of elderly
Insulin resistance	Increases	Increased risk of type 2 diabetes
Melatonin	Decreased production	Sleep disruption
Cortisol	May increase (variable)	Possible contribution to sarcopenia, metabolic syndrome

Gastrointestinal System

Parameter	Age-Related Change	Clinical Impact
Esophageal motility	Decreased amplitude, incomplete sphincter relaxation	Dysphagia, GERD
Gastric acid secretion	Decreased (20-30% of elderly have atrophic gastritis)	B12 malabsorption, increased infection risk
Gastric emptying	Slowed	Early satiety, decreased appetite
Small intestine	Mild villous atrophy, decreased absorptive surface	Mild nutrient malabsorption
Colonic motility	Decreased	Constipation (25-40% of elderly)
Hepatic mass/blood flow	Decreased 20-40% by age 75	Reduced drug metabolism (first-pass)
Gallbladder	Increased bile lithogenicity	Increased gallstone prevalence
Pancreatic exocrine function	Decreased enzyme secretion	Mild fat malabsorption

Integumentary System (Skin)

Parameter	Age-Related Change	Clinical Impact
Epidermal thinning	10-50% reduction	Thin, fragile skin; easy bruising
Dermal collagen/elastin	Decreased, cross-linked	Wrinkling, decreased elasticity, delayed wound healing
Subcutaneous fat	Decreased	Reduced insulation, increased hypothermia risk, pressure ulcer risk
Sweat glands	Decreased number and function	Reduced thermoregulation (heat intolerance)
Hair	Graying, thinning (androgenetic alopecia)	Cosmetic concerns
Nails	Thickened, brittle, slowed growth	Difficulty trimming, onychomycosis
Vitamin D synthesis	Reduced 75% by age 70	Vitamin D deficiency

Pharmacokinetics in Aging

Parameter	Change	Clinical Impact
Absorption	Minimal change	Generally not significant
Distribution	Decreased lean body mass, increased fat, decreased body water	Increased Vd for lipophilic drugs (benzodiazepines), decreased Vd for hydrophilic (lithium)
Albumin	Decreased (mild)	Increased free fraction of protein-bound drugs (warfarin, phenytoin)
Hepatic metabolism (Phase I)	Decreased CYP450 activity (30-50%)	Reduced clearance of many drugs
Hepatic metabolism (Phase II)	Relatively preserved	Conjugation reactions intact
Renal clearance	Decreased (parallels GFR decline)	Accumulation of renally cleared drugs
Half-life	Increased for most drugs	Longer duration of effect, increased toxicity risk

Homeostenosis (Loss of Reserve)

System	Reserve Loss	Manifestation Under Stress
Cardiovascular	Fixed stroke volume, reduced max HR	Delirium, falls, fatigue with mild illness
Renal	Limited GFR increase	Acute kidney injury with dehydration, nephrotoxins
Hepatic	Reduced clearance	Toxicity from medications at standard doses
Neurologic	Reduced neuronal reserve	Delirium with mild infection, medication
Immune	Reduced leukocyte response	Atypical presentation of infection (no fever, no leukocytosis)
Respiratory	Reduced forced expiratory volumes	Rapid decompensation with pneumonia
Thermoregulation	Impaired temperature regulation	Hypothermia with mild cold exposure; hyperthermia in heat
Musculoskeletal	Sarcopenia, osteopenia	Fracture with minimal trauma; fall from mild perturbation