What causes bodily functions to diminish as we age?

Why Bodily Functions Diminish with Aging

Aging is fundamentally driven by the gradual imbalance between damage accumulation and diminishing resilience mechanisms, where early in life homeostatic processes effectively maintain function, but later these compensatory mechanisms fade, allowing unrepaired damage to accumulate beyond functional thresholds. 1

The Biological Mechanisms of Aging

Hallmarks of Aging

The diminishment of bodily functions with age can be attributed to several interconnected biological hallmarks:

1. Genomic Instability - Accumulation of DNA damage over time 1, 2
2. Telomere Attrition - Progressive shortening of chromosome ends 2, 3
3. Epigenetic Alterations - Changes in gene expression patterns 1, 2
4. Loss of Proteostasis - Declining protein quality control 2, 3
5. Disabled Macroautophagy - Reduced cellular "self-cleaning" 2
6. Deregulated Nutrient-Sensing - Metabolic pathway dysfunction 2, 3
7. Mitochondrial Dysfunction - Declining energy production 1, 2
8. Cellular Senescence - Accumulation of non-dividing damaged cells 2, 3
9. Stem Cell Exhaustion - Reduced regenerative capacity 2, 3
10. Altered Intercellular Communication - Disrupted signaling between cells 2, 3
11. Chronic Inflammation - Persistent low-grade inflammation 2
12. Dysbiosis - Disruption of microbial communities 2

The Balance Between Damage and Resilience

The aging process represents a fundamental shift in the balance between two opposing forces:

• Damage Accumulation (Entropic Forces): Various forms of molecular and cellular damage that increase with time 1
• Resilience Mechanisms (Homeostatic Mechanisms): Compensatory processes that maintain biochemical balance 1

Early in life, resilience mechanisms effectively maintain homeostasis, but they begin to fade with advancing age, allowing unrepaired damage to accumulate beyond functional thresholds. This explains why the variance of aging phenotypes expands over time, with some individuals aging faster than others 1.

From Molecular Changes to Functional Decline

Microscopic to Macroscopic Progression

Aging begins at the molecular and cellular levels, with changes that scale up to affect organ and system function:

1. Molecular/Cellular Level:

   • Accumulation of advanced glycation end products (AGEs)
   • Mitochondrial dysfunction
   • Calcium channel alterations
   • Collagen deposition 1

2. Organ Level:

   • Atrial fibrosis
   • Impaired cardiac contraction
   • Capillary rarefaction
   • Reduced muscle mass 1

3. System Level:

   • Heart failure
   • Atrial fibrillation
   • Sarcopenia
   • Frailty 1

Mitochondrial Function and Aging

Mitochondrial dysfunction is a key contributor to aging:

• The mitochondrial theory of aging proposes that accumulated damage to mitochondria and mitochondrial DNA reduces energy availability and increases reactive oxygen species (ROS) production 1
• Studies have demonstrated that oxidative phosphorylation declines with aging in humans in the heart, skeletal muscle, and other tissues 1
• Reduced mitochondrial function is associated with mobility decline in older persons, mediated by a reduction of muscle strength 1

Biological Aging as a Dynamic Process

The Continuous Nature of Aging

Aging is not a discrete event but a continuous process that begins early in life:

• The gradual decay of biological systems is a hallmark of both aging and chronic disease progression that starts at the earliest stages of life 1
• Biological network and system decay lead to erosion of function and/or increases in stochastic behavior leading to increased variability/instability in network outputs 1
• At the molecular level, this can be quantified by the erosion of epigenetic landscapes across the human genome leading to alterations in gene expression patterns 1

Age-Related Changes in Daily Rhythms

Aging affects circadian rhythms and metabolic processes:

• As mice age, daily rhythms of locomotor activity, sleep, feeding, and several hormones dampen 1
• The ability of behavioral and hormonal rhythms to entrain to external environmental factors becomes impaired with age 1
• There is a reduction in the number of rhythmically expressed genes and a reorganization of rhythmic pathways in several metabolic organs during aging 1

Implications and Interventions

Understanding the biological mechanisms of aging opens possibilities for interventions:

• Exercise (both aerobic and high-intensity interval training) can reduce frailty in animal models 1
• Calorie restriction, antioxidants, and mTOR inhibitors have been shown to reduce frailty in naturally aging mice 1
• Some dietary interventions like protein restriction or intermittent fasting can reduce frailty, though effects may be sex-specific 1

Pitfalls and Caveats

• Interventions may have sex-specific effects, with many studies focusing primarily on males 1
• Polypharmacy (multiple medications) can increase frailty in aging mice, suggesting that de-prescribing may be beneficial in some cases 1
• Environmental factors like housing temperature can significantly affect metabolism and aging processes in research models, highlighting the complexity of studying aging 1

The heterogeneity in aging rates and manifestations underscores the importance of understanding the balance between damage accumulation and resilience mechanisms, which varies significantly between individuals 1.