February 26, 2020
Sophia Z. Liu, Amir S. Ali, Matthew D. Campbell, Kevin Kilroy, Eric G. Shankland1, Baback Roshanravan, David J. Marcinek & Kevin E. Conley
Age is characterized by a progressive loss of mobility, with muscle wasting (sarcopenia) and reduced endurance as key factors in this exercise intolerance.
Exercise training has been the gold standard for slowing or reversing sarcopenia.
Recent evidence indicates that dietary supplements may lead to improvements in both strength and endurance, which is a combination of adaptations that have not been possible with a traditional training program alone.5,6
Astaxanthin is a natural product with both antioxidant and anti-inﬂammatory properties 9–12 that has been found to increase strength and endurance.
Astaxanthin accumulates in tissues of animals in the food chain, such as salmon, that feeds on the marine algae, Haematococcus pluvialis 9 and is estimated to have been consumed at levels of 6 mg per day in populations with a salmon-based diet.15
Evidence for the beneﬁcial impact of AX on old muscle comes from a pilot study in mice found that AX accumulated in muscle with feeding and was associated with elevated muscle quality after exercise training on a treadmill.
Building on this pilot study there are a few studies that shows beneficial impact of AX in elderly humans.
To test a dietary formulation of astaxanthin, vitamin E, and zinc in combination with exercise training as an approach to elevate mobility, endurance, and strength in the elderly.6,8
To test the hypothesis that this astaxanthin-based formulation in combination with a functionally based exercise training program would activate improvements in both endurance and muscle strength, thereby providing a single approach to reverse loss of mobility and muscle properties in the elderly.
Twenty-nine-month-old male mice were treated with either 300 mg/(kg×day) astaxanthin (n = 10, Astareal, Inc. Moses Lake, WA, USA) or standard chow alone (n = 9).
The AX dose was determined for mice by scaling22 from the level found to be effective in rat studies.23
Exercise training occurred 3×/week on a 20° inclined treadmill at 10 m/min for 5 min at the start reaching 15 min in the ﬁnal 4 weeks of training.
In vivo muscle force of the gastrocnemius was measured as the maximum twitch and tetanic force during electric stimulations (200 Hz for 300 ms) at baseline and at 8 weeks in anaesthetized mice as described.24
The quadriceps muscle was frozen at the end of training to determine the level of astaxanthin.
Randomized, double-blind, placebo-controlled study was conducted at the University of Washington Medical Center and the Fred Hutchison Cancer Research Center.
Adults age 65–85 years old were recruited through public lectures, mailers, posted advertisements, and referrals from prior studies.
A total of 365 subjects were phone screened; 58 subjects enrolled in the study and were randomly assigned to groups.
Each subject had a physical examination, resting and exercise electrocardiogram, and blood testing to ensure that they were healthy and free from orthopedic and neuromuscular problems.
Treatment and dosing
The dietary formulation consisted of astaxanthin (12 mg), tocotrienol (10 mg), and zinc (6 mg; Astamed, Bellevue, WA) and was ingested as two capsules per day.
Additional components included in the formulation were Tocotrienols (vitamin E) and zinc.
Randomization and blinding
The subjects were assigned to the two treatment groups by an individual not associated with the study.
A random number generator provided the assignments.
Copies of the codes were held in separate locations that were not accessible to the investigators.
The assignment of the individual subjects to the treatment groups was not known to the participants or to the investigators until the study was completed.
The 12-week training program met 3× per week with a 10 min warm-up before and 5–10 min cool down period at the end of each session.
Treadmill training involved walking at ~1.3 m/sec with periods at a high treadmill incline of 9–12% grade (interval training) separated by periods of low incline walking at 5–7% grade (recovery).
Magnetic resonance imaging
Tibialis anterior (TA) muscle cross-sectional area (CSA) was determined from magnetic resonance images.
Five slices of each right limb were analyzed with NIH Image software.
Single muscle test: isometric ankle dorsiﬂexion
The TA muscle strength and contractile properties were determined on the right leg using a custom-built isometric exercise apparatus.
The subject performed a maximal voluntary contraction (MVC) using ankle dorsiﬂexion for ~5 sec by pulling on a strap that secured the foot to a force transducer platform.
An unpaired Student’s t-test was used to evaluate treatment vs. placebo in the pilot mouse study.
For the human study, a paired, 2-tailed t-test (pre-training vs. post-training change) was used with signiﬁcance assigned at α = 0.05 (P < 0.05).
The level of astaxanthin in muscle after the 8-week exercise program was signiﬁcantly elevated in the AX (236.7 ± 123.4 ng/g, n = 4) vs. the placebo (9.2 ± 9.2 ng/g, n = 6) treatment group.
Speciﬁc force (maximum twitch force/muscle cross-sectional area) was signiﬁcantly greater in AX vs. placebo-treated mice after training (P < 0.004, Table 2).
Increased interval stage exercise time demonstrates that the subjects in both treatment groups could exercise longer (greater time) and at a higher intensity (higher % grade) after training.
Walking distance in the 6 min walk also signiﬁcantly improved by ~8% in both groups with training (Figure 2B, Table S3).
A signiﬁcant change in human muscle strength, as measured by MVC (Δ14.4 ± Δ6.2% mean ± SEM, P < 0.02), is shown for the AX treatment group alone.
The TA muscle CSA (Δ2.7 ± Δ1.0%) also only increased in the AX treatment group (both image analysers found CSA differences at P < 0.01).
The ratio of these measures provides the muscle speciﬁc force (MVC/CSA), which trended to a higher value (Δ11.6 ± Δ6.1%, P = 0.053) in the AX treatment group alone.
No signiﬁcant change in muscle properties was found in the placebo treatment group (MVC, Δ2.9% ± Δ5.6%; CSA, Δ0.6% ± Δ1.2%; MVC/CSA, Δ2.4 ± Δ5.7%; P > 0.6 for all).
Functionally based exercise training combined with a formulation of natural anti-inﬂammatory and antioxidant compounds improved muscle strength and size in elderly subjects more than exercise training alone without sacriﬁcing the improvements in walking distance and endurance that typically accompany endurance training.
These results suggest that the potential for strength and endurance improvements in elderly muscle is realized when natural products that promote adaptation are combined with exercise training incorporating both resistance and aerobic components.
The end result is an approach involving functional exercise and a dietary formulation that can improve endurance, strength, and function to remedy the deﬁcits associated with sarcopenia that limit mobility in the elderly.
1. Lastayo PC, Marcus RL, Dibble LE, Smith SB, Beck SL. Eccentric exercise versus usualcare with older cancer survivors: the impact on muscle and mobility—an exploratory pilot study. BMC Geriatr 2011;11:5.
2. Brunjes DL, Kennel PJ, Christian Schulze P. Exercise capacity, physical activity, and morbidity. Heart Fail Rev 2017;22:133–139.
3. Conley KE, Jubrias SA, Cress ME, Esselman PC. Elevated energy coupling and aerobic capacity improves exercise performance in endurance-trained elderly subjects. Exp Physiol 2013;98:899–907.
4. Coffey VG, Hawley JA. Concurrent exercise training: do opposites distract? J Physiol 2017;595:2883–2896.
5. Nader GA. Concurrent strength and endurance training: from molecules to man. Med Sci Sports Exerc 2006;38:1965–1970.
6. Alway SE, Mccrory JL, Kearcher K,Vickers A, Frear B, Gilleland DL, et al. Resveratrol enhances exercise-induced cellular and functional adaptations of skeletal muscle in older men and women. J Gerontol A Biol Sci Med Sci 2017;72:1595–1606.
7. Trappe TA, Carroll CC, Dickinson JM, Lemoine JK, Haus JM, Sullivan BE, et al. Inﬂuence of acetaminophen and ibuprofen on skeletal muscle adaptations to resistance exercise in older adults. Am J Physiol Regul Integr Comp Physiol 2011;300: R655–R662.
8. Mankowski RT, Anton SD, Buford TW, Leeuwenburgh C. Dietary antioxidants asmodiﬁers of physiologic adaptations to exercise. Med Sci Sport Exer 2015;47:1857–1868.
9. Bell JG, Mcevoy J, Tocher DR, Sargent JR. Depletion of alpha-tocopherol and astaxanthin in Atlantic salmon (Salmo salar) affects autoxidative defense and fatty acid metabolism. J Nutr 2000;130:1800–1808.
10. Lee SJ, Bai SK, Lee KS, Namkoong S, Na HJ, Ha KS, et al. Astaxanthin inhibits nitric oxide production and inﬂammatory gene expression by suppressing I (kappa) B kinase-dependent NF-kappaB activation. Mol Cells 2003;16:97–105.
11. Park JS, Chyun JH, Kim YK, Line LL, Chew BP. Astaxanthin decreased oxidative stress and inﬂammation and enhanced immune response in humans. Nutr Metab (Lond) 2010;7:18.
12. Polotow TG, Vardaris CV, Mihaliuc AR, Goncalves MS, Pereira B, Ganini D, et al. Astaxanthin supplementation delays physical exhaustion and prevents redox imbalances in plasma and soleus muscles of Wistar rats. Nutrients 2014;6:5819–5838.
13. Malmsten CL, Lignell A. Dietary supplementation with Astaxanthin-rich algal meal improves strength and endurance— a double blind placebo-controlled study on male students. Carotenoid Science 2008;13:20–22.
14. Clark BC, Manini TM. Functional consequences of sarcopenia and dynapeniathe elderly. Curr Opin Clin Nutr Metab Care 2010;13:271–276.
15. Efsa. Opinion of the scientiﬁc panel on additives and products or substances used in animal feed on the request from the European commission on the safety of using coloring agents in animal nutrition. PART 1. General principles and Astaxanthin. The EFSA Journal 2005;291:1–40.
16. Tur JA, Colomer M, Monino M, Bonnin T, Llompart I, Pons A. Dietary intake and nutritional risk among free-living elderly people in Palma de Mallorca. J Nutr Health Aging 2005;9:390–396.
17. Ravena VG, Shimasaki H, Ueta N,Takahashi J. Interaction between a-tocopherol, tocotrienols and astaxantin in lipisomes, subject to lipid peroxidation. J Oleo Sci 2003;52:347–352.
18. Homma K, Fujisawa T, Tsuburaya N, Yamaguchi N, Kadowaki H, Takeda K, et al. SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deﬁciency. Mol Cell 52:75–86.
19. Brown DR, Gough LA, Deb SK, Sparks SA, Mcnaughton LR. Astaxanthin in exercise metabolism, performance and recovery: a review. Front Nutr 2017;4.
20. Fischer KE, Hoffman JM, Sloane LB, Gelfond JA, Soto VY, Richardson AG, et al. A crosssectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging (Albany NY) 2016;8:2370–2391.
21. Health US, 2016. National Center for Health Statistics. In Health, United States, 2016: With Chartbookon Long-term Trends in Health. Hyattsville, Maryland: CDC/National Center for Health Statistics/Ofﬁce of Analysis and Epidemiology; 2017.
22. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016;7:27–31.
23. Preuss HG, Echard B, Yamashita E, Perricone NV. High dose astaxanthin lowers blood pressure and increases insulin sensitivity in rats: are these effects interdependent? Int J Med Sci 2011;8:126–138.
24. Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, et al. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell 2013;12:763–771.
25. Parisi V, Tedeschi M, Gallinaro G, Varano M, Saviano S, Piermarocchi S, et al. Carotenoids and antioxidants in age-related maculopathy italian study: multifocal electroretinogram modiﬁcations after 1 year. Ophthalmology 2008;115:324–333, e322.
26. Satoh A, Tsuji S, Okada Y, Murakami N, Urami M, Nakagawa K, et al. Preliminary clinical evaluation of toxicity and efﬁcacy of a new astaxanthin-rich Haematococcus pluvialis extract. J Clin Biochem Nutr 2009;44:280–284.
27. Comhaire FH, El Garem Y, Mahmoud A, Eertmans F, Schoonjans F. Combined conventional/antioxidant “Astaxanthin” treatment for male infertility: a double blind, randomized trial. Asian J Androl 2005;7:257–262.
28. Kamezaki C, Nakashima A, Yamada A, Uenishi S, Ishibashi H, Shibuya N, et al.Synergistic antioxidative effect of astaxanthin and tocotrienol by coencapsulated in liposomes. J Clin Biochem Nutr 2016;59:100–106.
29. Trappe TA, Lindquist DM, Carrithers JA. Muscle-speciﬁc atrophy of the quadriceps femoris with aging. J Appl Physiol (1985) 2001;90:2070–2074.
30. Jubrias SA, Crowther GJ, Shankland EG, Gronka RK, Conley KE. Acidosis inhibits oxidative phosphorylation in contracting human skeletal muscle in vivo. J Physiol 2003;553:589–599.
31. PernegerTV.What’swrongwithBonferroni adjustments. BMJ 1998;316:1236–1238.
32. Merry TL, Ristow M. Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? J Physiol 2016;594:5135–5147.
33. Reeves ND, Maganaris CN, Longo S, Narici MV. Differential adaptations to eccentric versus conventional resistance training in older humans. Exp Physiol 2009;94:825–833.
34. Jubrias SA, Esselman PC, Price LB, Cress ME, Conley KE. Large energetic adaptations of elderly muscle to resistance and endurance training. J Appl Physiol (1985) 2001;90:1663–1670.
35. Mckinnon NB, Connelly DM, Rice CL, Hunter SW, Doherty TJ. Neuromuscular contributions to the age-related reduction in muscle power: mechanisms and potential role of high velocity power training. Aging Res Rev 2017;35:147–154.
36. Reeves ND, Narici MV, Maganaris CN. Musculoskeletal adaptations to resistance training in old age. Man Ther 2006;11:192–196.
37. Miller MS, Callahan DM, Toth MJ. Skeletal muscle myoﬁlament adaptations to agindisease, and disuse and their effects on whole muscle performance in older adult humans. Front Physiol 2014;5:369.
38. Desmedt JE, Godaux E. Ballistic contractions in man: characteristic recruitment pattern of single motor units of the tibialis anterior muscle. J Physiology 1977;264:673–693.
39. Klass M, Baudry S, Duchateau J. Voluntary activation during maximal contraction with advancing age: a brief review. Eur J Appl Physiol 2007;100:543–551.
40. Messi ML, Li T, Wang ZM, Marsh AP, Nicklas B, Delbono O. Resistance training enhances skeletal muscle innervation without modifying the number of satellite cells or their myoﬁber association in obese older adults. J Gerontol A Biol Sci Med Sci 2016;71:1273–1280.
41. Gonzalez-Freire M, De Cabo R, Studenski SA, Ferrucci L. The neuromuscular junction: aging at the crossroad between nerves and muscle. Front Aging Neurosci 2014;6:208.
42. Jang YC, Liu Y, Hayworth CR, Bhattacharya A, Lustgarten MS, Muller FL, et al. Dietary restriction attenuates age-associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD. Aging Cell 2012;11:770–782.
43. Nishimune H, Stanford JA, Mori Y. Role of exercise in maintaining the integrity of the neuromuscular junction. Muscle Nerve 2014;49:315–324.
44. von Haehling S, Morley JE, Coats AJS, Anker SD. Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2017. J Cachexia Sarcopenia Muscle 2017;8:1081–1083.