The term sarcopenia was originally created to refer age-related loss of muscle mass
with consequent loss of strength (Morley et al., 2001). There are now four international
definitions of sarcopenia (Cruz-Jentoft et al., 2010; Muscaritoli et al., 2010; Morley
et al., 2011). In essence they all agree, requiring a measure of walking capability
[either low gait speed or a limited endurance (distance) in a 6-min walk], together
with an appendicular lean mass of <2 SDs of a sex and ethnically corrected normal
level for individuals 20–30 years old. Sarcopenia is a prevalent health problem among
the elderly. On average, 5–13 and 11–50% of people aged 60−70 years and ≥80 years,
respectively suffer sarcopenia with higher prevalences (68%) been reported in nursing
home residents ≥70 years (Landi et al., 2012).
Sarcopenia needs to be differentiated from cachexia, which is a combination of both
muscle and fat loss and is usually attributable to an excess of catabolic cytokines
associated with a disease process (Argiles et al., 2010). Sarcopenia is a prime component
of the frailty syndrome, and both sarcopenia and frailty are associated with increased
disability, falls, hospitalization, nursing home admission, and mortality (Cesari
and Vellas, 2012; Landi et al., 2012).
Medical efforts to develop treatments aiming at preventing aging sarcopenia as well
as acute muscle atrophy and frailty in critical patients are considered a step forward
in public health. Several hormonal therapies have been proposed for this purpose,
such as those based on human growth hormone (hGH), IGF-1, testosterone, and stanozolol.
However, the secondary effects associated with these therapies make it necessary to
find novel non-toxic and non-hormonal therapies. In this way, elderly or bedridden
patients may improve muscle function and decrease the degree of dependence associated
with these populations. New drugs such as allopurinol or losartan (Sanchis-Gomar et
al., 2011), all of them approved by the Food and Drugs Administration (FDA) and actually
prescribed for the treatment of other diseases, could be useful in preventing loss
of muscle mass in the described susceptible populations yet new pharmacological targets
are needed.
Novel Pharmacological Targets to Prevent Sarcopenia: Emerging Pathways to be Explored
p16INK4a, NAD+, and sestrins pathways
In a recent manuscript, we proposed new targets for combating aging-related chronic
illness (Pareja-Galeano et al., 2014). An altered mitochondrial homeostasis through
reduced sirtuin 1 (SIRT1) activity induced by low nicotinamide adenine dinucleotide
(NAD+) levels has been recently advocated as a hallmark of muscle aging. A depleted
NAD+ pool could be the result of both the diminished NAD+ synthesis and increased
NAD+ consumption that occurs with age (Gomes et al., 2014). Treatment of mice with
NMN (an NAD+ precursor) can restore NAD+ levels and markers of mitochondrial function
that decay with age, reversing muscle mitochondrial senescence (Prolla and Denu, 2014).
Another novel potential biomarker arising from recent animal research is the p16INK4a
tumor suppressor. In geriatric mice, satellite cells lose their quiescent state owing
to deregulation of p16INK4a, whereas repressing p16INK4a restores muscle regenerative
capacity (Sousa-Victor et al., 2014). It is also known that p16INK4a expression increases
with age, and its greater expression has been linked to increased attrition (Tsygankov
et al., 2009). Recent evidence suggests that p16INK4a mRNA expression in peripheral
blood T-lymphocytes is upregulated by gerontogenic behaviors such as tobacco use and
physical inactivity, pointing to a critical role in age-related diseases (Song et
al., 2010).
Sestrins are a third recently discovered hallmark of aging sarcopenia. Mammalian cells
express sestrins (Sesn1, Sesn2, and Sesn3) in response to stress including DNA damage,
oxidative stress, and hypoxia. Sestrins can inhibit the activity of the mammalian
target of rapamycin complex 1 (mTORC1) through activation of AMP-dependent protein
kinase (AMPK) (Lee et al., 2013). Sestrins prevent sarcopenia, insulin resistance,
diabetes, and obesity. They also extend life and health span through activation of
AMPK, suppression of mTORC1, and stimulation of autophagic signaling (Lee et al.,
2013). We also proposed a possible role of the AMPK-modulating functions of sestrins
in the benefits produced by exercise in older subjects (Sanchis-Gomar, 2013a).
FGF21 and irisin: Potential therapeutic PGC-1α-related targets for aging and age-associated
diseases
Circulating body levels of irisin and fibroblast growth factor 21 (FGF21) increase
after cold exposure (Lee et al., 2014). Exercise-induced irisin secretion by working
skeletal muscles, which could have evolved from shivering-related muscle contraction,
might be a potential target of therapies designed to optimize weight control and metabolic
profile (Lee et al., 2014). Hence, targeting irisin and FGF21, and particularly the
key signaling molecule responsible for their secretion, the peroxisome proliferator-activated
receptor gamma coactivator-1 α (PGC-1α), could identify new candidates to be included
in the anti-aging armamentarium (Sanchis-Gomar, 2013b).
Irisin is an 112-amino acid glycoprotein, derived from the cleavage in working muscles
– and subsequent secretion to the circulation – of a PGC-1α-dependent type I membrane
protein, the fibronectin type III domain-containing protein 5 (FNDC5, 209 amino acids)
(Bostrom et al., 2012). Exercise-released irisin might act as a hormone either locally
within the muscle or targeting distant organs, particularly white adipose tissue,
and increase total energy expenditure (Bostrom et al., 2012). Irisin production increases
with chronic endurance exercise in mice and humans, and has been described to mitigate
obesity and diet-induced insulin resistance (Bostrom et al., 2012), yet its levels
decline with age (Sanchis-Gomar and Perez-Quilis, 2014). To explain exercise benefits
on insulin resistance, we recently proposed the following pathway starting in muscle
and targeting pancreatic β-cells: exercise-induced reactive oxygen species (ROS) → p38 → MAPK → PGC-1α → irisin → betatrophin → β-cell
regeneration (Sanchis-Gomar and Perez-Quilis, 2014). This pathway could also be affected
by aging. Interestingly, it has been also recently reported that disease-free centenarians
have increased serum irisin levels (Emanuele et al., 2014). Exercise induces the expression
of another PGC-1α – related hormone, FGF21 (Kim et al., 2013). Fasting drives the
production of FGF21 in the liver, where it induces PGC-1α expression, thereby stimulating
fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis. In effect,
mice lacking FGF21 are unable to fully induce PGC-1α expression in response to a prolonged
fast and show impaired gluconeogenesis and ketogenesis (Potthoff et al., 2009). Thus,
FGF21 plays an important role in ensuring metabolic regulation during progression
from fasting to starvation.
Besides metabolic deregulation and increased insulin resistance, another important
consequence of the aging process, reduced mitochondrial biogenesis, is also linked
to abnormal PGC-1α signaling (Sanchis-Gomar and Derbre, 2014). Importantly, an age-related
lack of muscle mitochondrial biogenesis can contribute to sarcopenia. PGC-1α knock-out
mice and aged rats show a strikingly similar muscle phenotype: they are unable to
express PGC-1α in response to the stimuli [i.e., exercise training, cold induction,
or thyroid hormone (triiodothyronine – T3 – treatment)] that naturally up-regulate
this molecule in young healthy rats (Derbre et al., 2012). Thus, maintaining normal
PGC-1α responsiveness might help prevent age-related lack of muscle mitochondrial
biogenesis (Derbre et al., 2012). In fact, several PGC-1α activators such as T3, cold
induction, 5′-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR), β-adrenergics,
cytokines, and exercise have been postulated to prevent aging sarcopenia (Figure 1).
The pioneer results by Lee et al. (2014) also suggest that targeting PGC-1α, e.g.,
using endocrine activators of brown fat function such as irisin and FGF21, might benefit
the treatment of other age-related conditions, particularly metabolic diseases.
Figure 1
Hypothesizing the role of FGF21-PGC-1α-Irisin axis in age-related conditions and sarcopenia.
See text for abbreviations.
Free-radical theory of aging questioned: Other molecular targets to prevent sarcopenia
are needed
Treatments for age-related and disease-related muscle loss might improve active life
expectancy in older people, and lead to substantial health-care savings and improved
quality of life (Rastogi-Kalyani et al., 2014). However, the results of recent epidemiological
studies (Perez et al., 2009) suggest that antioxidant supplementation does not lower
the incidence of major age-associated diseases and might even increase the risk of
death in some cases, have questioned the classic free-radical theory of aging (Gladyshev,
2014; Sanchis-Gomar et al., 2014). In fact, evidence mounts that ROS are important
mediators of the health-promoting, life-span-extending capacity of regular exercise,
as they play an important signaling role in a multitude of pathways including: angiogenesis,
vascular distensibility, and up-regulation of PGC-1α, PGC-1α/nuclear respiratory factor
1-stimulated mitochondrial biogenesis or cytoprotective “stress proteins” (heme oxygenase
1, heat shock proteins like HSP60 and HSP70) in muscle (Fiuza-Luces et al., 2013;
Sanchis-Gomar and Derbre, 2014). This means that antioxidant interventions are unlikely
to help combat sarcopenia. Moreover, anti-ROS strategies could even aggravate sarcopenia.
Thus, a major switch in strategy is proposed and investigators are now focusing on
myostatin and follistatin as promising molecular targets of anti-sarcopenia treatments.
Myostatin is a skeletal muscle-specific secreted peptide, pertaining to the transforming
growth factor-β (TGF-β) family member, that inhibits myoblast proliferation and consequently
muscle mass/strength by acting as a negative regulator of mTOR-signaling (Garatachea
et al., 2013). Mice treated with losartan, an angiotensin II receptor antagonist,
were protected against loss of muscle mass and this effect was mediated by activation
of the IGF-1/Akt/mTOR pathway (Sanchis-Gomar et al., 2011). These observations highlight
the importance of IGF-1/GH balance in longevity and may be of therapeutic interest
when targeting the undesirable effects of aging, especially at the muscle level (Sandri
et al., 2013).
Myostatin inhibition by agents capable of blocking the myostatin signaling pathway
such as ACVR2B (a soluble form of the activin type IIB receptor) could have important
applications in the treatment of human muscle degenerative diseases (Lee et al., 2005).
In addition, the growth and derived factor (GDF)-associated serum proteins-1 (GASP-1)
and 2 (GASP-2), which show competitive binding with proteins capable of inhibiting
myostatin, decrease muscle weight and impair muscle regeneration ability in mice (Lee
and Lee, 2013). Moreover, the inhibition of the myostatin/activin A signaling pathway
is sufficient to induce muscle hypertrophy and can be an effective therapeutic approach
for increasing muscle growth in disease settings characterized by satellite cell dysfunction.
Finally, the propeptide follistatin, a myostatin antagonist, might be a useful agent
for enhancing muscle growth in human therapeutic applications. In fact, increasing
follistatin circulating concentrations might help prevent and treat frailty, as well
as the cardiometabolic complications associated with androgen-deprivation therapy
(Sanchis-Gomar, 2013b).
Importance of Lifestyle Interventions to Delay Sarcopenia
Another important tool in the prevention of sarcopenia is physical exercise (some
of the molecular pathways involved have been discussed above). Particularly, exercise
training programs with resistance (strength) exercises (i.e., movements performed
against a specific external force that is regularly increased during training) are
especially useful for improving muscle mass or strength in the elderly (Liu and Latham,
2009), including in the oldest-old (people aged 90 years or over) (Fiatarone et al.,
1990).
On the other hand, autophagy also plays an important key role both in the modulation
of lifespan and sarcopenia (Madeo et al., 2010; Schiavi et al., 2013). Interestingly,
autophagy is required to maintain muscle mass and thus to prevent sarcopenia (Masiero
et al., 2009; Neel et al., 2013). In effect, failure of autophagy contributes to the
sarcopenic phenotype observed in premature aging (Joseph et al., 2013). For this reason,
physical exercise and calorie restriction are commonly recommended to prevent sarcopenia
since both of them modulate autophagy signaling (Marzetti et al., 2008; Wohlgemuth
et al., 2010).
Final Opinion
As an essential step for the prevention of aging-related diseases, and specifically,
sarcopenia, more basic research is needed on the main cellular hallmarks of muscle
senescence. There is a plethora of potential molecular signals that are candidates
to be targeted in future treatment strategies aiming at combating sarcopenia, a devastating
effect of aging that is often overlooked.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.