The following are excerpts from an article entitled The Impact of Sleep on Age Related Sarcopenia, made available by Julio Abucham, August 1st, 2015.


Reductions in duration and quality of sleep and increases in prevalence of circadian rhythm and sleep disorders with age favor proteolysis, modify body composition and increase the risk of insulin resistance, all of which have been associated with sarcopenia.
Data on the effects of age-related slow-wave sleep decline, circadian rhythm disruptions and obstructive sleep apnea (OSA) on hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-gonadal (HPG), somatotropic axes, and glucose metabolism indicate that sleep disorder interventions may affect muscle loss
Several protein synthesis and degradation pathways are mediated by growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, cortisol and insulin, which act on the cellular and molecular levels to increase or reestablish muscle fiber, strength and function. Age-related sleep problems potentially interfere intracellularly by inhibiting anabolic hormone cascades and enhancing catabolic pathways in the skeletal muscle.


Sarcopenia has been defined as a morphological and functional decline in lean body mass. Its operational diagnostic criteria are evolving, and no gold standard exists. Increasing evidence indicates that lean body mass is not the single factor related to reduced strength and impaired function (Visser et al., 2000). This parameter needs to be combined with poor strength or low gait speed to establish a sarcopenia diagnosis (Fielding et al., 2011).
Therefore, we propose that age-related sleep patterns and sleep disturbances contribute to skeletal muscle decline leading to sarcopenia. This novel hypothesis builds upon evidence linking polysomnography changes, insufficient sleep and sleep disturbances as they occur in older adults with the dysregulation of somatotropic, gonadal and corticotropic activity, as well as glucose metabolism, which disrupt the secretory pattern of hormones involved in muscle metabolism (Veldhuis and Iranmanesh, 1996, Van Cauter et al., 2004).

Hormonal Pathways & Muscle Metabolism Imbalance

GH and testosterone lead to nitrogen retention and protein synthesis, which promote muscle anabolism (Salomon et al., 1989, Bhasin et al., 1996). Consequently, GH, IGF-1 (an anabolic hormone secreted in response to GH secretion) and testosterone reductions can contribute to deteriorations in muscle mass and physical function.
Additionally, cortisol is related to muscle catabolism in aging, and sarcopenic subjects have elevated cortisol levels (Waters et al., 2008). Muscle weakness and wasting were strongly correlated with hypercortisolism. Regardless of age, patients with Cushing syndrome present body composition changes similar to sarcopenia in older adults (Miller et al., 2011).

Sleep in Advanced Age

Studies have demonstrated marked changes in sleep structure with aging, including a decrease in total sleep time and sleep efficiency, a decrease in the amount and intensity of slow-wave sleep (SWS), also named stage N3 non-REM sleep, and an increase in wake time after sleep onset (WASO) (Moraes et al., 2014).
Additionally, circadian rhythms modify with age and are associated with sleep disturbances. A decline in the amplitude of circadian markers, such as core body temperature, melatonin, and cortisol, has been reported (Zeitzer et al. 1999; Niggemyer et al. 2004;Monk 2005) and potentially influences sleep patterns and wakefulness (Huang et al., 2002, Luik et al., 2013, Hofman and Swaab, 2006).
Even at very advanced ages, successful aging appears to be directly related to good sleep quality (Tafaro et al., 2007, Gu et al., 2010, Jirong et al., 2013)...Long-term therapy for OSA using continuous positive airway pressure (CPAP) can increase lean body mass, suggesting sleep disorders’ important role in body composition changes and muscle mass maintenance (Munzer et al., 2010).

Sleep Related Metabolism Imbalances as Potential Contributors to Sarcopenia

As hormone imbalances are also observed with adverse sleep patterns and sleep disturbances, poor sleep and sarcopenia may be causally related...Sleep deprivation leads to an imbalance between catabolic and anabolic hormone secretions in animal models (Everson and Crowley, 2004, Andersen et al., 2005, Hipolide et al., 2006)
Muscle proteolysis is a consequence of poor sleep. Sleep deprivation for 72 h increases urinary urea excretion, an indirect measure of higher muscle catabolism (Kant et al., 1984). Paradoxical sleep deprivation in an animal model was causally associated with lower muscle fiber cross-sectional area (Dattilo et al., 2012). A caloric restriction protocol indicated that a reduction in sleep time does not affect absolute weight loss but minimizes the loss of adipose tissue and maximizes the decline in muscle mass (Nedeltcheva et al., 2010).
Sleep is directly involved in the secretion of GH (Sherlock and Toogood, 2007). Reduced amounts of SWS are largely responsible for the age-related reduction in GH secretion (Van Cauter et al., 2004). In males, 60-70% of GH secretion occurs during sleep, and secretion is timely associated with SWS (Van Cauter et al., 1998)
The initial reduction in GH secretion is an early phenomenon (at 20-39 years in men and 40-59 years in women) and occurs at a rate of 14% per decade (Blackman, 2000). This decline in GH secretion is mainly due to decreased nocturnal pulse amplitude (Van Cauter and Copinschi, 2000). After 60 years of age, spontaneous and pulsatile GH secretion is already 50-70% less than GH secretion in the third decade of life (O’Connor et al., 1996).
Another possible relationship between worsening sleep quality and lower nocturnal GH secretion has been derived from studies demonstrating that OSA negatively affects the growth hormone/insulin-like growth factor (GH/IGF) axis (Gianotti et al., 2002, Ursavas et al., 2007). In fact, OSA treatment with CPAP significantly increases GH release and IGF1 levels (Cooper et al., 1995, Saini et al., 1993, Hoyos et al., 2014).
It is recognized that age-related decline in androgens contributes to the development of sarcopenia (Ali and Garcia, 2014)...Additionally, imbalances in the HPA and HPG axis leading to unfavorable sex hormone profiles are associated with circadian rhythms and sleep disorders commonly observed in aged adults (Piovezan et al., 2013). Sleep debt affects the 24 h testosterone profile, which recovers poorly after sleep disruption in older adults (Andersen et al., 2011, Wittert, 2014).
Age-related poor sleep also enhances catabolic pathways. Evening cortisol levels increase after age 50, possibly as a consequence of sleep fragmentation and REM sleep decline (Balbo et al., 2010, Blackman et al., 2002)...Intermittent hypoxia during sleep observed in patients with OSA leads to chronic stress and influences circadian cortisol secretion (Edwards et al., 2014).
Additionally, increasing evidence confirms that sarcopenia is associated with insulin resistance, diabetes, and metabolic syndrome (Lee et al., 2011, Moon, 2014). Insulin promotes muscle anabolism and inhibits muscle proteolysis (Magkos et al., 2010, Punjabi et al., 2004, Guillet and Boirie, 2005, Boirie et al., 2001). Impaired glucose metabolism and the development of diabetes increase the risk of lean body mass decline in aged individuals (Rasmussen et al., 2006, Park et al., 2009, Park et al., 2007).
Likewise, sleep is intrinsically related to diabetes pathogenesis. A recent systematic review and meta-analysis showed that both quantity and quality of sleep can predict the risk of developing diabetes (Cappuccio et al., 2010). Insomnia has been associated with impaired glucose metabolism and diabetes (Vgontzas et al., 2009, Grandner et al., 2012, Keckeis et al., 2010, Gottlieb et al., 2005, Seelig et al., 2013).
CPAP therapy positively affects insulin sensitivity, leading to long-term improvement in glycated hemoglobin levels (Babu et al., 2005, Czupryniak et al., 2005, Dawson et al., 2008, Schahin et al., 2008, Harsch et al., 2004, Lam et al., 2010).

Integrating Cellular & Molecular Mechanisms to Explain How Hormonal Consequences of Sleep Impairment can Impact Muscle Recovery

Muscle protein synthesis and degradation pathways are possibly modulated by sleep patterns commonly observed in the elderly. Skeletal muscle growth and maintenance result from protein turnover and cell turnover (Sartorelli and Fulco, 2004). However, cellular turnover scarcely contributes to muscle fiber homeostasis in aged individuals (McCarthy and Esser, 2007, Rehfeldt, 2007, Karalaki et al., 2009). In aged muscle, protein turnover is the major physiological phenomenon involved in the balance between muscle anabolism and muscle catabolism (Sandri, 2008).
IGF-1-mediated signaling impairment related to decreased sleep quality and sleep disorders can contribute to muscle anabolism decline in advanced age groups (Sandri, 2008, Bonaldo and Sandri, 2013).
IGF-1 receptor binding in muscle activates phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt)...and stimulates protein translation by...activating mammalian Target of Rapamycin (mTOR) expression...this process enhances myocyte size and ribosome biogenesis (Bodine., et al 2001)
The mTOR pathway integrates diverse protein synthesis signals from growth factors, nutrients, muscle activity, hypoxia, and cellular stress.
Additionally, testosterone can inhibit myostatin, a TGF-beta family member that downregulates the IGF1-PI3K-Akt pathway and activates transcription factors of the forkhead transcription factor (FOXO) family, which induces protein degradation (McFarlane et al., 2006)...Hence, by directly blocking myostatin activity, testosterone can maximize muscle anabolism by interfering in diverse molecular pathways.
Cortisol leads to muscle atrophy by increasing muscle catabolism and reducing protein synthesis (Kayali et al., 1987, Millward et al., 1976)...related to ubiquitin-proteasome pathway activation, in which two muscle-specific E3 ubiquitin ligases regulated by FOXO, muscle atrophy F-box (MAFbx; also called atrogin-1) and MuscleRING-Finger-1 (MuRF-1), mark proteins for degradation by covalent modification with polyubiquitin chains (Auclair et al., 1997, Jackman and Kandarian, 2004, Pickart, 2001)
Cortisol can also inhibit IGF-1 synthesis in muscle and upregulates REDD1, inhibiting mTOR and S6K1, which reduces protein synthesis (Dehoux et al., 2004, Latres et al., 2005, Wang et al., 2006)
Consequently, age-related sleep changes and sleep disorders frequently observed at advanced ages reduce IGF-1 and testosterone secretions, which potentially decrease IGF-1/PI3K/Akt and mTOR activity and increase myostatin and REDD1 expression, decreasing muscle protein synthesis and enhancing muscle protein degradation. Furthermore, age-related increases in circadian cortisol levels can upregulate REDD1, which reduces mTOR pathway activity and decreases protein synthesis.
Furthermore, age-related increases in circadian cortisol levels can upregulate REDD1, which reduces mTOR pathway activity and decreases protein synthesis. Additionally, cortisol activates FOXO, enhancing atrogin-1 and MuRF-1 effects, which also promote muscle atrophy. Therefore, these cellular and molecular mechanisms build a model explaining how adverse sleep behaviors and sleep disorders are potentially associated with reduced skeletal muscle mass observed with aging (for details, see Figure 2) (Dattilo et al., 2011).

Frailty Phenotype & Sleep in The Elderly

Grip strength and slow gait speed are also parameters included in the sarcopenia diagnostic criteria. Frailty and sarcopenia share many risk factors, pathophysiological pathways and clinical consequences (Roubenoff, 2000, Nishiguchi et al., 2014, Vanitallie, 2003).
Biochemical mechanisms related to reductions in testosterone levels, chronic inflammation, imbalanced GH secretion and increased cortisol levels are possible pathways shared by frailty and sarcopenia in their relationship with sleep disturbances in the elderly (Haddad et al., 2005, Schakman et al., 2009, Ceda et al., 2005, Cawthon et al., 2009, Hyde et al., 2010, Yeap et al., 2013).

Sleep as a Possible Mediator for Some of the Effects of Physical Exercise on Sarcopenia

Physical exercise is currently the most important single intervention able to reduce frailty risk and positively impact sarcopenia parameters and physical function in the elderly. Indeed, the magnitude of the effects of exercise on muscle strength and endurance are not significantly different across age groups (Landi et al., 2014)...Randomized controlled trials (RCT) testing the effects of exercise have consistently demonstrated improvements in lean mass, muscle strength and physical capacity in older adults (Fielding et al., 2002, Suetta et al., 2008, Strasser et al., 2009, Goodpaster et al., 2008).
resistance training has acute effects on objective sleep parameters, decreasing arousal index and possibly leading to higher sleep consolidation in healthy older men (Viana et al., 2012). Acute physical exercise may also increase SWS, consequently improving sleep homeostasis, although this finding is more consistently found in young adults (Youngstedt, 2005, Naylor et al., 2000). Benefits in self-reported sleep quality and objective sleep parameters in older adults with sleep complaints are possible long-term effects of exercise (King et al., 1997, Singh et al., 1997, King et al., 2008)
the complex sleep-exercise relationship may be bidirectional, and sleep potentially impacts physical performance during exercise (Driver and Taylor, 2000). Independently of the direction of this association, the exercise-sleep relationship in older adults possibly explains part of the theoretical anabolic effects of interventions to ameliorate sleep or treating sleep disorders by means of physical exercise practices in advanced age groups.
Improvements in subjective and objective sleep variables may also reciprocally enhance exercise performance in older subjects, although this hypothesis requires further clarification (Dzierzewski et al., 2014). Greater ability to exercise as a result of better sleep may explain the synergistic effects of sleep and exercise to enhance physical performance and diminish disability in older adults (Weaver et al., 1997). Healthy habits are more present in persons engaged in long-term exercise practices, and a better lifestyle can improve sleep habits (Youngstedt, 2005).
A greater recruitment of pharyngeal muscle fibers during exercise possibly reduces airway collapse during sleep, which could explain the benefits of exercise training in the OSA, independently of BMI changes (Giebelhaus et al., 2000). Otherwise, sarcopenia has been hypothesized as a major factor in age-related OSA pathophysiology (Bliwise et al., 2010). Therefore, an additional and indirect effect of exercise in the improvement of sarcopenia parameters may be due to the AHI reduction observed as a result of the exercise-related anabolic effects in the upper airway muscles and pharyngeal anatomy.
In fact, transient hormonal spikes in post-workout periods potentially enhance muscle hypertrophy more critically than persistently elevated hormonal levels (Schoenfeld, 2013). This finding theoretically supports the advantages of pulsatile and transient hormonal secretions mediated by sleep and exercise over hormonal replacement therapy proposals.


The rationale for studying possible associations between sleep and the risk of sarcopenia is the fact that few interventions have proven effective in the recovery of muscle mass and function in the elderly (Ali and Garcia, 2014). Preventive or therapeutic options for sarcopenia are limited to lifestyle interventions, such as nutritional recommendations and physical activity (Malafarina et al., 2013, Morley et al., 2010, Montero-Fernandez and Serra-Rexach, 2013).
Recovering the circadian and sleep-related mechanisms of hormone release could be an alternative and effective strategy for physiologically activating the somatotropic and HPG axis functions, recovering muscle function at advanced ages.
By recognizing the circadian rhythms of anabolic and catabolic hormones, preventive and therapeutic options for sarcopenia that target the restoration of favorable sleep patterns can be developed. Sleep is a possible mediator in the development of sarcopenic symptoms with age.
Aaron TanasonComment