Interventions for Human Frailty: Physical Activity as a Model

By: Linda P. Fried

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

Date: 2016


  • 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.


  • 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 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.

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