Aging is commonly used to name the progressive decay of organism’s function in later life. Aging has an indistinct onset and a highly variable inter-individual progression. Today as well as in all recovered marks of human culture the inevitable end of life has provided a strong incentive to find measures to postpone it. While substantial progress has been made in extending the average expected lifespan, rejuvenation (or preserving youthfulness) still remains a concept more than a reality. The extension of lifespan among those we consider long-lived is not very impressive compared with the gain for those that previously died at a younger age. The latter accomplishment came by improving living conditions and by preventing as well as combating major health threats until modern times, poor nutrition, and infectious diseases. Throughout the post-industrial nations and now also in developing countries, this has led to a dramatic change in the population composition by age (demography). The inflation of the aged over the younger cohort and the exponential growth of care expenditures, lead to an economic and social stress on society that needs to be addressed. Focus has therefore shifted from lifespan to healthspan, to extend the years that older people can continue to be independent, participate and contribute to society rather than experience life quality deterioration and consume resources because of poor health. To meet these challenges, the WHO recently classified aging-induced disorders as diseases (World Health Organization (WHO)2019, 2020), an action intended to pave the way for the development of rational interventions to impede or even halt the aging-induced decline of health (The Lancet Diabetes Endocrinology (LDE), 2018).

In this future perspective we will touch upon the recent major demographic changes and biological processes considered to be involved in aging, and then devote the main part to sarcopenia, i.e., the dissipation of muscle function and mass, a conspicuous trait of the aged human phenotype. We chose sarcopenia because it is a facultative decay occurring also in healthy aging individuals yet it is accelerated by comorbidity, hospitalization, and a sedentary lifestyle. According to World Health Organization (WHO) (2000), sarcopenia is one of the major causes of loss of independence and a very significant risk factor for developing other morbidities at older age.

Over the past one and a half centuries, the average human life span has almost doubled in high-income countries (HICs) and middle-and-low-income countries (MILOICs) are following. According to the Gerontology research group¹, a low boundary estimate of the number of people alive today at older age than 109 years is close to 500. They are all born early in the 20th century and since then the world population has increased from 1.6 to 7.8 billion (United Nations (UN), 2019). Due to this enormous increase in human phenotypes (molded out of the genotypes), it is believed that the number of supercentenarians will grow rapidly and that the apparent ceiling of human longevity around 120 years will be pushed forward. However, this raises issues with the interpretation of the lifespan extension during the 19th–20th centuries and the scarcity of reliable more distant historic data as well as to what extent longevity is heritable (Oeppen and Vaupel, 2002; Crimmins, 2015; Dong et al., 2016; Kontis et al., 2017; Ben-Haim et al., 2018; Kaplanis et al., 2018). As Sweden has one of the best backlogging population statistics, we will use this here as a framework to discuss changes to lifespan and mortality across the past centuries and, in addition, how health care intervention is consumed by age and sex in the year 2019 (Figure 1).

Since 1751, life expectancy at birth has more than doubled in Sweden (Figure 1A). The increase was particularly fast in the 20th century (Figure 1B) but as we approach and surpass 80 years in lifespan expectancy at birth (Figure 1A) and in agreement with several other HICs, lifespan extension is now slowing down (Figures 1A,B; Dong et al., 2016). By comparing mortality by age and sex we can see that the extended lifespan is due to the curbing of early life mortality (see inset in Figure 1C; <5 years; 3–5% 1751–1760 down to 0.01–0.32% in 2019) meaning that today with a few exceptions all those born alive will reach puberty. At menarche/puberty and throughout a major portion of the reproductive period (here defined as the period between 15 and 49 years), mortality remains low and remarkably stable at 0.6–1.2% in 1751–1760 and 0.2–0.6% in 2019 until age 35–39. This “reproductive mortality plateau” present in the Swedish population statistics both from 1751–1760 and 2019, is in no way exclusive to Sweden (Perls et al., 2002; Crimmins, 2015) and suggests that the human population has been selected from those that had good health through a sufficiently long period to reproduce and nurture a surplus of children also under more challenging and impoverished conditions². The second major change is the shift from ∼50 to ∼70 years of age as the breakpoint when mortality start to increase rapidly (Figure 1A); at above 75–80 years of age the mortality is high still today (idem). When comparing the changes in mortality between 1751–1760 and 2019 (Figure 1C) with health care interventions by age and sex in 2019 (Figure 1D), we can conclude that the much-improved survival in early life and at older age both are reflected in a comparatively larger consumption of health care interventions of these age groups. This indicates that we have been more successful in curbing mortality than to decrease morbidity (here defined as an instance of intervention with a treatment diagnosis) over the past centuries and consequently that aging is a key co-factor for the concurrent and future health provisions by society (Ben-Haim et al., 2018; Partridge et al., 2018). Lifespan extension and the parallel change to the fertility rate (Supplementary Figure 1A) have altered the demographic profile toward older ages (Supplementary Figure 1B), forcing society to recognize aging as a major factor for dependence and morbidity. In order to facilitate the development of effective preventive medicine that can postpone morbidity and increase healthspan, we need reliable predictive biomarkers of morbidity that also consider the impact of aging (Beekman et al., 2010; Deelen et al., 2013).

A very simplistic description is that aging is the accumulation of non-degraded waste (e.g., myelin bodies, lipofuscin, and amyloid) and unrepaired damage to cellular/extracellular constituents with a run-down of cellular energy production, and the gradual exhaustion of the replicative capacity forcing cells into state of non-responsiveness/senescence (Figure 2). This gradual decay has a variable pace both between tissues within individuals as well as between individuals and lead to the disintegration and finally death of the organism. Why aging occurs is a much debated issue (Kirkwood and Melov, 2011; Azzu and Valencak, 2017) but humans in HICs currently live more than twice the time it takes to reproduce and nurture a growing human population and the older ages beyond the reproductive era make up an increasingly large part of the lifespan strongly associated with morbidity and decay of function. While any benefit for the human species of growing old remains to be evidenced, closing the gap between health- and lifespan is not an issue of opposing views. Studies devoted to shed light on the heritability of growing old indicate that only a modest 25% of the variability in lifespan can be accounted for by heritage (Wijsman et al., 2011; Kaplanis et al., 2018; Partridge et al., 2018). However, as we push the expected lifespan toward the ages of those that are most long-lived (100+) and who did not experience the same increase in lifespan over the past centuries, the genetic constraint of human lifespan may become increasingly important (Barzilai et al., 2010; Beekman et al., 2010; Kenyon, 2010; Rajpathak et al., 2011). This assumption is supported by the fact that most long-lived humans appear to be protected against some of the hazards conferring morbidity and death among more short-lived humans (Beekman et al., 2010; Rajpathak et al., 2011). Aging is a complex polygenic trait and already the non-exhaustive listing of 24 genes with a strong association with longevity in humans (Partridge et al., 2018) is extensive enough to generate a very large number of different genotypes and, when coupled with environmental impact, an even larger set of phenotypes. To close some of the gap between health- and lifespan at older ages, a deeper understanding of the genetics of aging is needed (Atwood et al., 2003; Kirkwood et al., 2011).

Calorie/dietary restriction (CR/DR) is the most robust and general (across mammalian and non-mammalian species) intervention known to retard aging and is therefore a useful tool to dissect the processes underlying aging and aging-induced traits like sarcopenia (an extended review of CR with references is available in the Supplementary Material). Laboratory work in the early 20th century (for references see Speakman and Mitchell, 2011) showed that reducing calorie or dietary (CR/DR restriction) intake by 10%-45% increased lifespan by up to 50% in many invertebrate and vertebrate species, implicating that this intervention intercepted with highly conserved mechanisms of systems biology involved in the aging of organisms. In mammals, CR reduces the incidence of common morbidities such as cardiovascular diseases and cancer (main causes of death at older ages in HICs) and, thus, seems to extend healthspan to a similar extent as lifespan. In mammals like small rodents CR will retard body growth and, if initiated in adulthood, lower body weight, an adaptation which will affect both lean body mass and, in particular, adipose tissue (Duffy et al., 1997; Cameron et al., 2011). Rodents are endothermic and respond to CR with a lowering of body temperature and torpor (idem), accompanied by alterations in the endocrine system with decreased levels of TSH, T4, and T3 (Araujo et al., 2009) (HPT axis), growth hormone and IGF-1, and lower levels of blood glucose and insulin as well as increased insulin sensitivity (Cameron et al., 2011; Azzu and Valencak, 2017). Metabolically, there is a shift toward β-oxidation of fatty acids (Bruss et al., 2010). This metabolic shift has also been argued to be the main reason for the lower levels of oxidative (ROS) stress in subjects under CR (Speakman and Mitchell, 2011). The increase in metabolic activity of white adipose tissue (WAT) under CR is accompanied by an upregulation of key lipid enzymes and a browning of the white fat (Bruss et al., 2010; Fabbiano et al., 2016). The decrease in amount of WAT under CR also lowers levels of leptin and increases levels of adiponectin (Hardie, 2011). The decreased production of ATP (higher AMP:ATP ratio) and increased adiponectin signaling will both induce AMP-activated protein kinase (AMPK) (Hardie, 2011), which will depress the anabolic drive by inhibition of mTOR (idem). mTOR (mammalian/mechanistic target of rapamycin) is a key protein of the TORC complex (TORC1/2) regulating cell growth by promoting protein translation and inhibiting the FOXO family of transcription factors (idem). In addition to inhibiting mTOR through inducing AMPK and decreasing insulin/IGF-1 signaling, CR induces also another family of proteins, the sirtuins (Sirt 1-6) (Guarente, 2011). The sirtuins [nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases] are metabolic sensors that stimulate mitochondrial biogenesis, lower oxidative stress, inhibit mTOR and induce both FOXO and autophagy-lysosomal activity, reduce oxidative stress and DNA damage, and increase p53 activity (idem). Thus both actions by the sirtuins and the AMPK-driven inhibition of mTOR will activate the FOXO family of transcription factors, paving the way for increased regulated proteolysis through the ubiquitin-proteasome system (UPS) and increased degradation of proteins, molecular complexes, and organelles through the autophagy-lysosomal pathway conferring a more rapid turnover of cellular constituents (Martins et al., 2016; Maiese, 2021). FOXO proteins also upregulate cellular oxidative defense and have an inhibiting function on proteins involved in cell cycling (idem). Combined, the CR-mediated decrease in oxidative stress, increased biogenesis of mitochondria, and accelerated turnover of cellular constituents may slow the wear and tear that generates the cumulative build-up of unrepaired damage during aging. Trials with chemical compounds that show the promising extension of lifespan in model organisms are all partial mimetics of CR and targets mTOR (rapamycin, Miller et al., 2014), AMPK (metformin, Weiss et al., 2018), or indirectly both sirtuins and AMPK by inhibiting mitochondrial function (resveratrol, Price et al., 2012).

Trials with CR on long-lived species such as primates (Colman et al., 2009; McKiernan et al., 2011) and humans (Most et al., 2017) remain limited, for obvious reasons. However, those to date show promising outcomes, suggesting that CR mediates its effects through the same evolutionary conserved mechanisms as described above for small rodents. Furthermore, several of the gene variants associated with human longevity (Partridge et al., 2018) are genes implicated in the beneficial outcome of CR, such as FOXO(3A), the growth hormone-IGF-1 signal transduction pathway, and proteins involved in cell cycling (Guevara-Aguirre et al., 2018).

Changes that take place in the skeletal muscle during aging have received comparatively more attention than muscle innervation, especially in studies of humans. The process that instigates sarcopenia is still the subject of debate (Gutman and Hanzlikova, 1972), at more advanced stages a multitude of alterations are present in peripheral innervation as well as in the target tissue, which makes it quite challenging to determine cause and effect. Most of our understanding of molecular and cellular mechanisms in myofibers and the muscle scaffold during aging stem from work done on laboratory animals. For a detailed account on myogenic mechanisms in the sarcopenia processes, we refer to some recent reviews (Larsson et al., 2019; Christian and Benian, 2020; Pascual-Fernández et al., 2020). Briefly, early studies on sarcopenia (previously referred to as old-age-muscle-atrophy or senile-muscle-atrophy) in laboratory small rodents and humans revealed that aging is accompanied by a loss of myofibers, atrophy preferentially affecting fast twitch (type II) myofibers, and a fiber type grouping—features that increase with advancing chronological age. Further, myofibers in aged subjects display irregularities of the end plate, increased content of lipid droplets and of secondary lysosomes, and an increasing number of fibers that show a myosin expression pattern intermediate between type I and type II (hybrid fibers) (Lexell et al., 1983; Bowen et al., 2015; Larsson et al., 2019). Concurrent alterations in the amount of fat and connective tissue, vasculature, and thickening of the capillary basement membrane have been described indicating that the muscle scaffold is impacted by the aging process (McGregor et al., 2014; Larsson et al., 2019). On most of these variables, there is a good agreement between observations made in humans and small rodents. For obvious reasons, a major obstacle in human studies is the limitation of performing longitudinal studies and hence most studies use a cross-sectional design. This design does not take into account the individual variation in factors that are known to have a huge impact on sarcopenia, such as genetic make-up, socio-economic changes, physical activity, and medical history (Mitchell et al., 2012).

In addition to the well-established age-related structural changes, another hallmark of the aged human muscle is a diminished muscle remodeling capacity. This will impact the possibility of the skeletal muscle to respond to age-associated changes in the innervation. An attenuated remodeling capacity is evidenced by the dissipating capacity to recover from immobilization-induced muscle mass loss with increasing age (Figure 3; Wall et al., 2013) and is further demonstrated by a diminished adaptation to both resistance and aerobic exercise with age. For example, it was recently reported that 12 weeks of heavy resistance training in very old men and women (age 83–94) had no effects on type II fiber area, satellite cell content, or myonuclear density, supporting the observation of reduced plasticity at advanced ages (Karlsen et al., 2019).

An important factor in this context is anabolic resistance, which refers to blunted protein synthesis in response to anabolic stimuli such as exercise and nutrients. Anabolic resistance has been attributable to attenuated TORC1- dependent and TORC1- independent mechanisms (e.g., MAPK/ERK pathways) and includes effects on ribosomal biogenesis (Cuthbertson et al., 2005; Fry et al., 2011). Other mechanisms that may participate in the progressive attenuation of remodeling capacity with age is the accumulation of somatic mutations in satellite cells (SCs; myogenic stem cells) in human muscles (Franco et al., 2019). An accumulation rate of 13 somatic mutations per genome and year was reported to occur and these mutations were also detected in the adult myofiber (Franco et al., 2018). The latter observation suggests that, through SC fusion, mutations propagate into the mature multinucleated muscle fiber and impact skeletal muscle cell function. In addition, several groups have reported a reduced number of SC in aged muscle, especially around type II fibers, concurrent with a reduced proliferation and differentiation capacity of the SCs (Verdijk et al., 2014; Franco et al., 2019). A linear correlation between number of SCs and fiber size has been reported in aged individuals (Mackey et al., 2011; Franco et al., 2019), and a reduced number of SCs seems to be associated with diminished muscle remodeling capacity (Suetta et al., 2013). This is further underlined by evidence that depletion of SCs in animal models leads to an increase in the amount of fibrotic connective tissue and adipocyte infiltration, two hallmarks of the aged skeletal muscle (Franco et al., 2019). From a mechanistic point of view, a blunted activation of SCs in aged individuals is observed in parallel with an attenuation of Notch signaling, which is possible to reverse through an activation of this pathway (Carlson et al., 2009; Suetta et al., 2013). An increased expression of the cellular senescence marker p16 has also been detected in SCs in aged individuals compared to young individuals (Carlson et al., 2009; Suetta et al., 2013). Other well-established age-associated changes in the muscle scaffold include alterations of the cellular composition (infiltration of inflammatory cells, adipocytes, and fibroblasts), as well as increased amounts of connective tissue and intra-myocellular lipids. This affects the microenvironment and the crosstalk between cells (Latroche et al., 2017). Moreover, the intra-myocellular lipids and their derivatives have been shown to induce mitochondrial dysfunction and increase generation of reactive oxygen species as well as the development of the age-related chronic low-grade systemic inflammation (Kalinkovich and Livshits, 2017). Changes in the micro-milieu are plausible mechanisms in both the dissipation of muscle function and the decreased ability to regenerate in response to various stimuli (Hiona and Leeuwenburgh, 2008; Pillon et al., 2013). Moreover, as observed in SCs from older individuals, changes in the micro-milieu could also introduce chromatin alterations and DNA methylation changes, which may add to changes induced by somatic mutations (Bigot et al., 2015; Franco et al., 2019).

By using participants of the population-based Uppsala longitudinal study of adult men (ULSAM) cohort (Skoglund et al., 2020), changes in skeletal muscle expression in a set of candidate genes involved in muscle remodeling was analyzed longitudinally. At age 70, an activation of the pathways associated with UPS was observed but this response was significantly attenuated by age 88. The gene expression pattern at 70 years was defined as beneficial since the subjects maintained their muscle fiber histology and appendicular lean body mass until advanced age. This is consistent with observations made in small rodents, where it was proposed to be related to an initial increased remodeling due to denervation/re-innervation followed by incapacitation at advanced age resulting in an increased number of permanently denervated myofibers (Altun et al., 2012). A similar response has recently been demonstrated in human skeletal muscle (Piasecki et al., 2018).

The literature clearly shows that both genetic and environmental factors are closely intertwined and together will define the individual’s phenotype at different ages. Both the onset and the progression of sarcopenia are highly variable between subjects owing to genetic and environmental/life-style factors (Degens and Korhonen, 2012; Bann et al., 2015; Khanal et al., 2020; Figures 3A,B). Muscle strength and the amount of muscle mass in adult life are to a large extent due to genetic factors; heritability estimates of >50% are not uncommon (Zempo et al., 2017). A number of genes such as ACTN3, ACE, and VDR have been associated with skeletal muscle phenotypes (Pratt et al., 2019; Singh and Gasman, 2020). GWAS studies have linked genetic polymorphisms to both muscle growth/lean body mass and [handgrip] strength. However, linkage to establish their importance to skeletal muscle-trait variation has generally been identified as small, especially with advancing age (Carmelli and Reed, 2000). Notably, while some of the so-far identified genes associated with the above metrics have a function in neuromuscular transmission and neuronal plasticity, most of the strongly associated genes have a hitherto unknown function in skeletal muscle (idem). A problem with these linkage/association studies is that they address metrics such as static handgrip strength and lean body mass, while the association between genes/genetic polymorphism and the age-of-onset and pace-of-progression of sarcopenia remains to be addressed.

Since population-based studies clearly demonstrate that environmental factors such as nutrition together with neuroendocrine changes are associated with loss of both muscle function and mass as well as the tissue integrity of skeletal muscle during aging, many intervention regimens have been targeted to correct or override these changes (Larsson et al., 2019). Physical activity in adult life will, in contrast to a sedentary life-style, preserve muscle function better at old age in both humans and rodents (Trappe et al., 1996; Bann et al., 2015; Drey et al., 2016; Figure 3). However, sarcopenia also affects top athletes (Trappe et al., 1996; Gava et al., 2015; Drey et al., 2016; Piasecki et al., 2016; Ganse et al., 2020) and analysis of data on track and field records (both cross-sectional and/or longitudinal records) of master athletes discloses that there is steady decline in power of about 1% per year between 30–70 years of age. At more advanced age, most datasets show an accelerated drop (1–2% per year) (Trappe et al., 1996; Gava et al., 2015; Ganse et al., 2020) and the slope of the decrease is steeper for ballistic power demanding sports than running sports (Gava et al., 2015). This re-emphasizes that recruitment/contraction speed and coordination may be more sensitive to aging than strength and mass and, further, that once sarcopenia becomes clinically overt the process has probably been ongoing for decades but clinically compensated for by intrinsic mechanisms. The significance of physical activity is, however, underscored by the fact that the loss of muscle mass and function is accelerated during periods of immobilization (Wall et al., 2013). This is further aggravated by the diminished muscle remodeling capacity of aged individuals in the recovery following mobilization-induced muscle loss (Suetta et al., 2013). Even though the response to exercise is to some extent blunted at older age, it is still the best documented intervention strategy (Bao et al., 2020; Grgic et al., 2020). There are conflicting opinions concerning the benefits of strength vs. endurance training or if a combination of both tailored to the individual is optimal (Trappe et al., 1996; Mitchell et al., 2012; Bowen et al., 2015; Drey et al., 2016; Karlsen et al., 2019). Resistance-type training has the largest impact on skeletal muscle mass but aerobic exercise also attenuates aging-induced changes and it preferentially stimulates metabolic pathways such as oxidative capacity including mitochondrial density, structure, and function. Importantly, exercise increases insulin sensitivity by increasing sarcolemmal glucose transporter (Glut 4) levels, augmenting metabolic flexibility, and reducing the risk of development of insulin resistance (type 2 diabetes) (Biensø et al., 2015; Bowen et al., 2015; Cartee et al., 2016). Exercise also decreases fat infiltration, increases SC number, and appears to facilitate the maintenance of the NMJ integrity at advanced age (Valdez et al., 2010; Power et al., 2016; Franco et al., 2019). Furthermore, increased physical activity has positive effects on age-related diseases linked to secondary sarcopenia such as chronic heart failure and obstructive lung diseases (Coats, 1996; Bernard et al., 1998).

It could be argued that exercise, and especially resistance exercise, activates mTOR pathways and one of key changes identified by CR/DR models is a reduced mTOR activity which seems to attenuate the aging process. An interesting observation in humans by Phillips et al. (2013) that individuals with the greatest increase in lean mass gain following resistance training had a suppressed mTOR signaling over the training period. Moreover, the overall effects of exercise are largely coherent with the findings in the CR models, with increased PGC-1 expression and activation of AMPK (Egan and Zierath, 2013; Bowen et al., 2015). More knowledge is needed to understand how the activities of these signal pathways contribute to the aging process in skeletal muscle and the effects of counteracting exercise regimes. Importantly not all individuals respond to the same extent to exercise (i.e., high versus low responders) and meta-analyses provide evidence that very old individuals remain responsive to resistance-type training with increases in strength that occurs without any changes in muscle mass (Beckwée et al., 2019; Karlsen et al., 2019). The latter suggests that exercise-induced changes in advanced age may be more related to neuromuscular function and/or intrinsic contractility machinery than increase in muscle mass (Biolo et al., 2014). This may have implications for the design of physical activity programs for the elderly population.

Sarcopenia is a facultative trait of the aged human. The underlying process of this disorder which becomes clinically overt during the 5th–7th decades of life may start as early as during the 3rd decade as judged by decreases in muscle strength and power. We argue that sarcopenia has a neurogenic origin while in the clinically manifest disorder the innervating MNs, target myofibers, and muscle scaffold are probably components of a viscous cycle were it is challenging to decide on what is cause or consequence. We have pointed to gaps in knowledge, such as the crosstalk between motor axons, terminal Schwann cells, and myofibers in the denervation/re-innervation processes that lead to a loss of MU and muscle weakness during aging. To capture the early events of sarcopenia, we will need to modify the operational definition and introduce the concept of the pre-clinical phase that should include more functional metrics and validated biomarkers for susceptibility to develop severe sarcopenia.

It is clear that the rapidly changing composition of the human population will impact incidence and prevalence of diseases and aging-induced disorders and that closing the gap between healthspan and lifespan should be our next priority. To address this we must fill knowledge gaps in our understanding of the biology of aging including sarcopenia. Linkage studies of genetic polymorphisms associated with age-of-onset and pace-of-progression of sarcopenia are missing but warranted to shed light on the large difference in impact between individuals and why some respond to interventions while others do not.

We argue that preventive measures to intercept with biological aging are lagging behind efforts to treat manifest clinical outcomes of aging. To accomplish compliance with prescription of preventive measures, we need to identify reliable predictors to convince individuals to enroll in intervention programs that may be life-long.

Both authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

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.