By: Linda P. Fried

In: Cold Spring Harbor Perspectives in Medicine, 2016 Jun 1.

Date: 2016

Summary

• Life span has expanded.
  • Added about 30 years in life span over the last 100 years.
• Mostly due to:
  • Public health interventions targeting infectious diseases.
  • Decreased early childhood and maternal mortality.
• Challenge: how to maximize health and vitality across expanded lifespan.
  • Compression of morbidity to the latest point in the human life.
    • Prevention of chronic diseases.
      • At every age and stage of life.
      • If you arrive at 70 at good health, reasonable chance of remaining healthy.
    • Prevention and treatment of frailty.
  • Model intervention: physical activity.

Key Takeaways

• Homeostasis and resilience = healthy physiological and biological systems.
  • Ability to adapt, respond to injury and stress.
• These systems are complex.
  • Systems mutually affect or regulate each other.
• Frailty = dysregulated systems.
  • Loss of adaptive capacity.
  • Especially apparent in response to stressors, challenges.
  • Distinct phenotype.
  • Mostly associated with dysregulation of energy (low strength, low energy, weight loss).
  • Independent predictor of mortality.
• Fix: physical activity.
  • Improves energy production and use.
  • Complex, low-risk intervention.
  • Preserves or improves many functions compromised in frailty.

Key Concepts

Age and disease

• Disease and chronological age not necessarily tied together.
  • Disease (of specific organ systems) can be a process distinct from aging.
    • Atherosclerotic disease of the heart, brain, and peripheral vasculature.
• Disease is not inevitable with advance in age.
  • Many chronic diseases are preventable.
  • Subject to risk factors: physical activity, smoking, diet, inflammation.
• Both disease and age are factors in mortality.
  • Chronic disease are reliable predictors of mortality.
  • Age becomes a factor above 85 years of age.
• Concept of biological and chronological age.
  • Altered physiological regulation and function across multiple systems.

Frailty

• After about age 70, a new phenotype emerges: frailty.
  • Independent predictor of mortality.
• Medical syndrome.
  • A constellation of symptoms and signs.
  • When present in critical mass predicts outcomes and identifies a distinct underlying pathophysiology.
  • Predicts outcomes more than any other one or two factors.
• Symptoms:
  • Muscle weakness (grip strength).
  • Slowed gait (time to walk about 15 feet).
  • Low physical activity (<270 kcal/week).
  • Sense of low energy or exhaustion (“everything is an effort”).
  • Unintentional weight loss (>10 pounds).
• Chronic, progressive.
  • Twice as prevalent in women as men.
• By age 85, 25% of population manifests 3-5 components of frailty.
• Progression:
  • Begins with declines in strength, walking speed, physical activity.
  • Progresses to low energy or exhaustion and unintended weight loss.
• Frailty is the consequence of a trade-off between robustness and fragility.
  • Robustness contributing to homeostasis and maintenance of functionality.

Underlying mechanisms of frailty

• Frailty emerges from the dysregulation of complex adaptive systems.
  • Systems that maintain organismal homeostasis and resilience.
    • Resilience: response to stress and injury.
  • Systems decline with age.
• Physiological systems that decline:
  • Hormonal deficiency (estrogen, testosterone, IGF-1).
  • Impaired insulin sensitivity.
  • Increased inflammation (cytokine excess).
• Biological systems that decline:
  • Mitochondrial dysfunction (lower ATP).
• No dominating patterns.
  • Only predictor is the number of systems dysregulated.
  • Not any particular system.
• Complex.
  • Change in systems affect multiple components of the frailty phenotype.
  • Systems mutually affect or regulate each other (feed-forward feed-back loops).
• Dysregulation > threshold number = critical loss of homeostatic adaptive capacity = frailty.
  • Frailty is an emergent state.
• Loss of resilience becomes apparent in response to stressors, challenges.
• Frailty = marker of a severe end stage of biologic aging.
  • Underlying dysregulation of the complex dynamical systems that maintain a resilient organism.
  • Dysregulation of the system becomes evident in the presence of stressors.
  • Leading to adverse health outcomes occur when the system is challenged.

Interventions

• Interventions targeting only one of the dysregulated systems have not been able to prevent frailty.
  • Evidence that frailty is a complex system problem.
• Energy dysregulation: the critical entry point to development of frailty.
  • Altered energy intake (diet).
  • Unintentional weight loss.
  • Physical exhaustion.
  • Muscle weakness.
  • Altered glucose metabolism.
  • Lower muscle efficiency.
  • Decline in mitochondrial function.
• Intervention should focus on improving energy production and use.
  • Shift the entire complex system of function.
• Physical activity: complex intervention.
  • Physical activity itself is correlated with lower mortality.
    • Reverse: decline in physical activity both predicts and worsens frailty.
  • Physical activity preserves or improves many different functions compromised in frailty.
  • Physical activity maintains mitochondrial function, lowers ROS.
  • General organization of metabolic apparatus is far better preserved in individuals who exercised regularly.
  • Delay onset and progression of frailty.
  • Low-risk.
  • Simultaneously up-regulates many systems that mutually regulate each other in combination.
  • The whole organism could be re-tuned to a higher functional level.