Understanding Fatigue: From Myth to Science

1. Old PeopleWant to DanceFatigue In Older Person. From Myth to . . Art to . . ScienceLuigi Ferrucci, MD, PhDLongitudinal Studies SectionClinical Research BranchNIA/NIH Baltimore - MD

2. Metabolism [From Greek metabolē, change, from metaballein, to change : meta-, meta- + ballein, to throw.] Fatigue Definition: A subjective feeling, which is typically the result of working, mental stress, jet lag or active recreation, and also boredom, disease and lack of sleep. It may also have chemical causes, such as poisoning or mineral or vitamin deficiencies. Definition: The chemical processes occurring within a living cell or organism that are necessary for the maintenance of life: some substances are broken down to yield energy for vital processes while other substances, necessary for life, are synthesized.

3. Ethymology of Fatigue from Fr. fatigue "weariness," from fatiguer "to tire," from Latin fatigare, originally "to cause to break down," later, "to tire out," from reconstructed adj. fati-agos "driving to the point of breakdown," from Old Latin fatis (of unknown origin, related to adv. affatim "sufficiently" and to fatisci "crack, split") + root of agere "to drive" (see act). Fatigues appeared 1836, from sense of a soldier's non-military duties (1776).

4. But Also. . . From Fata or Fatim, the God of Destiny Fatigue may be interpreted as inextricably connected with the destiny of being a living creature, the ultimate dispersion of the energy critical for the life of the individual in the collective energy that pervades the Universe. The overturn of Entropy over the Order of life. Rest counteracts Entropy and recreate Order.

5. WOMAN WITH YELLOW HAIR Pablo Picasso, Dec. 27, 1931

6. Fatigue and Pain from the Original Sin Sistine Chapel (Apostolic Palace, Vatican City) - Michelangelo 1508-1512

8. Duccio da Buoninsegna (1280) Crucifixion Scene from the Maestà Altarpiece

9. Perpetual fatigue… The Sisyphus Myth Sisifo - Tiziano Vecellio, 1548-1549 Madrid, el Prado

10. The Man with a Hoe Bowed by the weight of centuries he leans Upon his hoe and gazes on the ground, The emptiness of ages in his face, And on his back, the burden of the world. The Man with a Hoe By Edwin Markham

11. Viktor Vasnetsov. The Unsmiling Tsarevna. 1916-1926. Vasnetsov Memorial Museum, Moscow

12. Fatigue as a means of enlightenment… . . . The Ecstasy of St Theresa Gianlorenzo Bernini (1652). Santa Maria della Vittoria (Rome).

13. Hercules Twelve Labours

14. “As a result of having painted for so long a time, if he had to read a letter or some other small thing, he was obliged to hold it above his head. ‘After four tortured years, more than 400 over life-sized figures, I felt as old and as weary as Jeremiah. I was only 37, yet friends did not recognize the old man I had become.’ Michelangelo died on February 18, 1564.” Sistine Chapel - Michelangelo 1508-1512

15. Wanderer's Nightsong Up there all summits are still. In all the tree-tops you will feel but the dew. The birds in the forest stopped talking. Soon, done with walking, you shall rest, too. . . Johann Wolfgang von Goethe (1776-1780)

16. “... continual hard labor deadens the energies of the soul . . . like the uncultivated soil, brings forth thorns and thistles . . . . nature herself becomes almost exhausted, and we care but little whether we live or die.” Maria W. Stewart September 21, 1832 – Public speech at the New England Anti-Slavery Society (in Franklin Hall, Boston)

17. FatigueTransitioning from Art to Science • Fatigue has to do with energy. Lack of energy or, even better, “impending lack of energy”. Energy here is used in broad terms, including but not limited to physical and mental energy. • Conceptually, if not physiologically, the sense of fatigue is a bottleneck, where different conditions of energetic inadequacy converge. Whether physical and mental exhaustion differ semantically is questionable. • Fatigue calls for a change in behavior that results either in a decline of energy utilization or an improvement of energy production. The signal for changing behavior is positive in a physiological state but can be highly problematic in pathology and, perhaps, in aging. • In thermodynamic terms, fatigue may be interpreted as entropy overcoming order.

18. Unknown Other Thermogenesis 2% – 3% Gastric Emptying Post-Prandial Thermogenesis 8% -12 % Delayed Thermogenic Zenith and Reduced Thermogenesis (-10%) An Energetic View of Fatigue 100 Percentage of Energy Utilization per Day Lean Body Mass Physical Activity 15% - 30% Reduced Phys. Activity (- 46%) Enzymatic Activity Es. Na+K+ATPase Reduced RMR (- 44%) 50 BMR 60% – 70% 60 MEB 50 40 30 RMR ( k c a l / K g / d i e ) 20 10 0 0 0 20 40 60 80 100 (Wilson AA, J Appl Physiol 2003) Age (years)

19. 2 1 Excessive Mortality 0 -1 20 25 30 35 40 45 Basal Metabolic Rate (kcal/hr/m2)

20. 40 35 Resting Metabolic Rate, (kcal/m2/hr) 30 Predicted RMR by decade 25 10 20 30 40 50 60 70 80 90 100 40 35-49 years at study entry <35 years at study entry 35 50+ years at study entry Resting Metabolic Rate, (kcal/m2/hr) 30 25 10 20 30 40 50 60 70 80 90 100 Age,(years)

21. An Extended Model of Energetic Frailty MVO2max Post-Prandial and Other Thermogenesis Fatigue (How much energy is left beyond walking?) Physical and Cognitive Activities (Walking, Talking, Watching, Thinking, etc.) Competitive Physical Activity Efficiency Intense Physical Activity Moderate Physical Activity Extra Energy for Unstable Homeostasis (Homeostatic Effort) FITNESS Low Physical Activity Behavior Theoretical Minimum Energy Requirement For Homeostasis (Age, Sex, Body Composition and Physical Activity) Sedentary State Behavioral Disability Bed Rest

22. An Extended Model of Energetic Frailty MVO2max • The answer to the “fatigue question” • How close are we to the energetic limits? • depends on the reciprocal relationship between • three factors: • Max aerobic capacity (MVO2) • Resting Metabolic Rate (RMR) • Net Cost of a Standard Task (MCSF) (Efficiency=1/MCSF) • MVO2 is inversely correlated to Fatigue • RMR is directly correlated to fatigue • Efficiency is inversely correlated to fatigue • In addition, there should be perceptual component probably modulated at the CNS level (inflammation, depression etc.). How Close to MVO2? Physical and Cognitive Activities (Walking, Talking, Watching, Thinking, Digesting, etc.) Metabolic Cost Standard Task Extra Energy for Unstable Homeostasis (Homeostatic Effort) Theoretical Minimum Energy Requirement For Homeostasis (Age, Sex, Body Composition and Physical Activity) RMR

23. Between Hypotheses and Guesses • Inadequately high basal metabolic rate (RMR) is a risk factor for mortality because it is a marker of homeostatic effort • Energy efficiency in mobility tasks contributes to disability, especially when energy availability is limited • Fatigue establishes a connection between the biological processes that generate and transform energy and the usual level of physical activity of an individual • Whether a measure of MVO2 max conveys already enough information to estimate the threshold for fatigue is unknown. This is a critical information because by altering the fatigue threshold we could modulate activity behavior in daily life.

24. Old People Want to Dance

25. “I would Sleep but Thou Must Dance. . .” (Theodor Storm 1817 - 1888) Cited in Thomas Mann Tonio Kroger.