Frailty/APA Style Essay/Ch.8

profileycam08
fraility_sarcopenia_article_004_.pdf

R

F

D M B

a

A R R A A

K I I F S N I

C

h 1

Ageing Research Reviews 36 (2017) 1–10

Contents lists available at ScienceDirect

Ageing Research Reviews

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / a r r

eview

railty and sarcopenia: The potential role of an aged immune system

aisy Wilson ∗, Thomas Jackson, Elizabeth Sapey, Janet M. Lord RC-ARUK Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital

irmingham, Edgbaston, Birmingham, B15 2WD, UK

r t i c l e i n f o

rticle history: eceived 22 November 2016 eceived in revised form 26 January 2017 ccepted 31 January 2017 vailable online 20 February 2017

eywords: mmunesenescence nflammaging railty arcopenia eutrophil

a b s t r a c t

Frailty is a common negative consequence of ageing. Sarcopenia, the syndrome of loss of muscle mass, quality and strength, is more common in older adults and has been considered a precursor syndrome or the physical manifestation of frailty. The pathophysiology of both syndromes is incompletely described with multiple causes, inter-relationships and complex pathways proposed. Age-associated changes to the immune system (both immunesenescence, the decline in immune function with ageing, and inflam- mageing, a state of chronic inflammation) have been suggested as contributors to sarcopenia and frailty but a direct causative role remains to be established. Frailty, sarcopenia and immunesenescence are commonly described in older adults but are not ubiquitous to ageing. There is evidence that all three con- ditions are reversible and all three appear to share common inflammatory drivers. It is unclear whether frailty, sarcopenia and immunesenescence are separate entities that co-occur due to coincidental or potentially confounding factors, or whether they are more intimately linked by the same underlying

nactivity cellular mechanisms. This review explores these possibilities focusing on innate immunity, and in partic- ular associations with neutrophil dysfunction, inflammation and known mechanisms described to date. Furthermore, we consider whether the age-related decline in immune cell function (such as neutrophil migration), increased inflammation and the dysregulation of the phosphoinositide 3-kinase (PI3K)-Akt pathway in neutrophils could contribute pathogenically to sarcopenia and frailty.

© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license

(http://creativecommons.org/licenses/by/4.0/).

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1. Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2. Sarcopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.3. Relationships between frailty and sarcopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2. Pathophysiology of sarcopenia and frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1. Regulation of muscle mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

3. Ageing of the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.1. Role of increased systemic inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3.1.1. Inflammatory cytokines, IL-6 and TNF� . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.1.2. Anti-inflammatory cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1.3. Leukocytes, sarcopenia and frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

∗ Corresponding author. E-mail address: [email protected] (D. Wilson).

ttp://dx.doi.org/10.1016/j.arr.2017.01.006 568-1637/© 2017 The Authors. Published by Elsevier B.V. This is an open access article u

1. Introduction

1.1. Frailty

The concept of frailty is probably recognised by most biogeron- tologists but its emerging importance as a hallmark of ageing has led to a more rigorous medical definition of physical frailty.

nder the CC BY license (http://creativecommons.org/licenses/by/4.0/).

2 search

i p f 2

i T i t l i s h o s p r p 1 b o ( r

e p F w c o a a l e i s

c d a 2 o r r c i i o a b

r F m E s H i

1

o m d

D. Wilson et al. / Ageing Re

‘A medical syndrome with multiple causes and contributors that s characterized by diminished strength, endurance, and reduced hysiologic function that increases an individual’s vulnerability or developing increased dependency and/or death’ (Morley et al., 013).

This definition describes the syndrome but does not attempt to nterpret the condition or its underlying biological mechanisms. wo intrinsically different models of frailty have been proposed n an attempt to operationalise the syndrome. The first model, he frailty phenotype model, was proposed by Fried and col- eagues (Fried et al., 2001). This suggests that a step-wise increase n self-reported disability is analogous with an increasing frailty tate and correlates with adverse health outcomes such as death, ospitalisation and falls. Fried demonstrates that the presence f 3 components, out of a total of 5 (unintentional weight loss, elf-reported exhaustion, weakness, slow walking speed and low hysical activity), has predictive power in identifying mortality isk. Fried extrapolates this to suggest that the presence of 3 com- onents in a person identifies them as frail and the presence of

or 2 components as pre-frail (Fried et al., 2001). The model has een validated by Fried and independent groups with concurrent r predictive validity assessed in 17 different samples or cohorts Bouillon et al., 2013), but no attempt has been made to assess the eliability of the phenotype.

Conversely Rockwood et al. suggested that frailty was not a cat- gorical phenomenon but best described as a dynamic, continuous rocess of deficit accumulation and as a result they proposed the railty Index (Mitnitski et al., 2001). The most striking difference ith the Fried definition of frailty was that any variable could be

onsidered a deficit as long as it was associated with adverse health utcomes, increased in prevalence with age into the tenth decade nd had a prevalence of at least 1% which did not saturate in older ge. Using this model Rockwood showed there was a greater corre- ation of time to death with frailty index rather than age (Mitnitski t al., 2001). The Frailty Index has also been widely tested for valid- ty with concurrent or predictive validity assessed in 13 different amples or cohorts (Bouillon et al., 2013), but not reliability.

One of the difficulties in deciding upon the most elegant and linically applicable model is that each model describes a slightly ifferent population. The Frailty Index has better discriminatory bility for adults with moderate and severe frailty (Rockwood et al., 007). This is probably due to its broader approach to the diagnosis f frailty and the inclusion of cognitive and psychosocial markers ather than solely relying on physical markers. There are also higher ates of frailty reported with the Frailty Index, likely due to the ontinuous nature of the model (Song et al., 2010). This may make t a better objective marker of the assessment of the efficacy of an ntervention. The frailty phenotype may have utility in identifying lder adults at risk of disability. It has been suggested that these ssessment instruments should not be considered as alternatives, ut rather as complementary.

Both the Frailty Index and the Frailty Phenotype are utilised in esearch but the more global concept of frailty as described by the railty Index is probably better accepted in the gerontology com- unity. This is reflected in recent diagnostic and screening tools,

dmonton Frail Scale and PRISMA 7, including the assessment of everal domains of health (Rolfson et al., 2006; Raiche et al., 2008). owever, the relative ease of utilising the Frailty Phenotype means

t is still used in research as a method of identification of frailty.

.2. Sarcopenia

Sarcopenia can be considered as one of the main physical drivers f frailty or perhaps even a precursor state if it is present without a edical classification of frailty as described above. As with frailty,

efinitions of sarcopenia have evolved over time reflecting greater

Reviews 36 (2017) 1–10

understanding of the condition. The current broadly accepted def- inition includes the effects on function as well as including muscle mass and strength:

‘A syndrome characterised by progressive and generalised loss of skeletal muscle mass and strength with a risk of adverse out- comes such as physical disability, poor quality of life and death.’ (Cruz-Jentoft et al., 2010a).

Similar to the frailty phenotype the European Working Group on Sarcopenia in Older People (EWGSOP) recommend categorising sarcopenia into pre-sarcopenia, sarcopenia, and severe sarcopenia depending on the presence of certain criteria. They suggest that the pre-sarcopenia stage is characterised by low muscle mass with no impact on muscle strength or physical performance, whereas the sarcopenia stage is low muscle mass with either low muscle strength or low physical performance and severe sarcopenia is the presence of all three criteria (Cruz-Jentoft et al., 2010a).

The cut off point for each criterion is not currently standardised and is dependent on both the method of measurement and the researcher. It is generally accepted that low physical performance is defined as a gait speed of less than 0.8m/sec. Low muscle strength is usually defined by handgrip strength of less than 30 kg for men and less than 20 kg for women (Cruz-Jentoft et al., 2010a; Cruz-Jentoft et al., 2010b). Low muscle mass is usually measured by a skeletal muscle mass index with a variety of cut offs quoted in the literature ranging from 7.23 kg/m2 to 8.87 kg/m2 in men and 5.45 kg/m2 to 6.42 kg/m2 in women (Baumgartner et al., 1998; Newman et al., 2003; Chien et al., 2008; Cruz-Jentoft et al., 2010a). The diversity in the cut offs, particularly in defining low muscle mass, utilised in research has led to huge disparity in the prevalence of reported low muscle mass with prevalence reported as between 3.3 to 41.5% in community populations over 65 (von Haehling et al., 2010). This has been recognised by the EWGSOP who have recommended that more research is urgently needed in order to obtain good reference values for populations around the world.

The inclusion of both muscle mass and strength within the defi- nition of sarcopenia has partially occurred in response to extensive research which has shown that whilst loss of muscle mass is asso- ciated with loss of muscle strength, the relationship is not linear; the decline in strength is more rapid than the concomitant loss of muscle mass. Goodpaster et al. demonstrated in a community dwelling population aged between 70 and 79 that muscle mass declines at 0.5-2% per annum compared to 2–4% loss of muscle strength (Goodpaster et al., 2006). Thus age-related changes in the quality of the muscle may be as important as the reduced mass and reduced muscle quality, notably loss of type II fibres, reduced mitochondrial mass and increased fat infiltration, may contribute to loss of muscle strength and power (Narici and Maffulli, 2010). Potentially a more inclusive definition of sarcopenia may incorpo- rate the loss of muscle mass, reduced muscle quality and a loss of functional strength, as shown in Fig. 1, which depicts age-related changes occurring within the muscle from the whole muscle level through to a cellular level and how these contribute to the loss of muscle mass, quality, strength and power.

1.3. Relationships between frailty and sarcopenia

The relationship between frailty and sarcopenia is not yet fully characterised but these conditions share many of the same clini- cal outcomes, associations and suggested pathophysiology. Despite this, sarcopenia is considered a component of frailty but frailty is not considered a component of sarcopenia. However, there is considerable overlap between the defining criteria of the Frailty

Phenotype and sarcopenia. Severe sarcopenia as defined by EWG- SOP is pre-frailty by the Fried phenotype. Sarcopenia is often considered a pre-cursor syndrome or the physical component to frailty.

D. Wilson et al. / Ageing Research Reviews 36 (2017) 1–10 3

F relat c ross s

g b t r ( 7 l t e ( a

t a ( r o i t c i f b T a i

r t t t E f l t f t i

ig. 1. Age related changed occurring within the muscle. Figure depicting the age ellular level and their impact on muscle mass, quality, strength and power. CSA – c

Sarcopenia is reported to be twice as common as frailty in the eneral population (von Haehling et al., 2010). The prevalence of oth conditions is dependent on population and definition. Using he EWGSOP definition and criteria of sarcopenia the prevalence anges from 4.6%, community dwelling men in the UK aged 68–76 Patel et al., 2014), to 68%, male Italian nursing home residents over 0 (Landi et al., 2012). A recent systematic review of frailty preva-

ence in a community population (Collard et al., 2012) reported he range to be 4.0%, independently mobile men over 65 (Cawthon t al., 2007), to 59.1%, community dwelling Dutch older than 70 Metzelthin et al., 2010). The calculated weighted average of frailty s defined using the Frailty Phenotype is 9.9% (Collard et al., 2012).

Research has shown that in frail community dwelling adults he most common positive Fried criteria was slow gait speed (43%) nd weakness (54%), the functional defining criteria of sarcopenia Rothman et al., 2008). It has also been reported that the relative isk of developing weakness and low activity was higher than devel- ping any other frailty defining criteria over 7.5 years of follow up n initially non-frail women (Xue et al., 2008). This suggests that heoretically while it is possible to have frailty without sarcopenia linically it is unlikely. However, a recent isolated report investigat- ng the concordance of frailty and sarcopenia demonstrated that railty was more common than sarcopenia and the concordance etween frailty and sarcopenia was poor (Reijnierse et al., 2016). his is the only literature investigating the concordance of frailty nd sarcopenia but is contrary to previous understanding and an solated report.

Importantly both frailty and sarcopenia are considered partly eversible conditions. Several epidemiological studies have shown hat whilst transition between lesser and greater frailty is always he most frequent outcome, a number of participants will transi- ion from greater to lesser frailty (Gill et al., 2006; Fallah et al., 2011; spinoza et al., 2012; Lee et al., 2014). Health status and baseline unction is important, as those with poor mobility at baseline in a ongitudinal study experienced faster acceleration of their frailty

han those with good mobility (Fallah et al., 2011). The reversal of railty has also been demonstrated in intervention studies. A mul- ifactorial intervention in community dwelling frail adults resulted n a significant difference in frailty prevalence between the two

ed changed occurring within the muscle from a whole muscle level through to a ectional area.

groups who were identical at baseline. Of note, the intervention was specific to the individual depending on their positive frailty criteria at baseline assessment, for example those scoring for weight loss would be assessed and managed by a dietician, consistent with a personalised medicine approach. Importantly, this study reported an actual reduction in diagnosis of frailty in the intervention group not just a slowing of progression (Cameron et al., 2013). It is also possible to improve components of frailty and sarcopenia. Several resistance exercise programmes have documented improvements in gait speed and strength in groups of frail older adults, with pro- grammes of 8–12 weeks able to reverse loss of muscle strength equivalent to that lost over 20 years (Fiatarone et al., 1994; Liu- Ambrose et al., 2004). Improved understanding of the processes underlying sarcopenia may allow the development of even more efficacious and targeted interventions.

2. Pathophysiology of sarcopenia and frailty

The pathophysiology of both sarcopenia and frailty is com- plex. Proposed models for both syndromes incorporate multiple causes, inter-relationships and elaborate pathways (Fried et al., 2009; Cruz-Jentoft et al., 2010a). However, both syndromes are incompletely characterised and there is insufficient understanding of the underlying cellular mechanisms driving the development and maintenance of states of frailty and sarcopenia. Sarcopenia is better understood than frailty largely due to its effects being con- centrated on a single system, the neuromuscular system, and for this reason it has been suggested as a physical model of frailty.

2.1. Regulation of muscle mass

Our current understanding of the regulation of muscle mass is predominately based on data from animal studies, with much less known of the key regulatory processes in human muscle. Stud-

ies in rodents suggest that muscle synthesis is intrinsically linked with muscle atrophy via the PI3k-Akt pathway which is central to both processes (Schiaffino and Mammucari, 2011). Muscle synthe- sis is activated by insulin-like growth factor 1 (IGF-1) binding to

4 D. Wilson et al. / Ageing Research Reviews 36 (2017) 1–10

F a pro r a stat

I w ( t 2 s o m u ( ( p

a p u ( t d a i t i a S c e 2

h b a

ig. 2. Relationships between inflammaging, sarcopenia and frailty. Figure depicting ole for inflammaging within the creation and maintenance of frailty and sarcopeni

GF-1 receptor which triggers the activation of a signalling path- ay including PI3k, Akt, and the mammalian target of rapamycin

mTOR), which in turn phosphorylates S6 kinase and other fac- ors which promote protein synthesis (Schiaffino and Mammucari, 011). There are multiple modulators of the pathway, both intrin- ic and extrinsic. Intrinsic regulators include S6 kinase 1 inhibition f insulin receptor substrate (IRS) (Harrington et al., 2004) and TORC2 upregulation of Akt (Sarbassov et al., 2005). Extrinsic reg-

lators include: amino acids which can directly activate mTORC1 Kim et al., 2008; Sancak et al., 2008) and beta adrenergic agents Kline et al., 2007) and Wnt7a which both upregulate the PI3k-Akt athway (von Maltzahn et al., 2012).

Muscle atrophy via both the ubiquitin proteasome pathway nd autophagy lysosomes is centrally regulated by forkhead box roteins (FoxO). FoxO when present in the nucleus induces the biquitin E3 ligases atrogen-1 and muscle RING finger protein-1 MuRF-1) (Williamson et al., 2010) which cause myofibril degrada- ion. FoxO also regulates ATG genes which promote mitochondrial egradation via autophagy (Polager et al., 2008). As expected there re multiple modulators of these pathways and arguably the most mportant is the effect of Akt on FoxO: Akt phosphorylates FoxO and ransports it from the nucleus to the cytoplasm preventing it from nducing either E3 ligases or ATG genes (Stitt et al., 2004; Huang nd Tindall, 2007; Jang et al., 2007). Myostatin, via the action of mad 2 and 3, upregulates FoxO (McFarlane et al., 2006) and mus- le disuse produces neuronal nitric oxide synthase (nNOS) which nhances FoxO3 mediated transcription of E3 ligases (Suzuki et al., 007).

The majority of studies investigating sarcopenia in humans ave suggested that loss of muscle mass is primarily driven by a lunted synthetic response to both feeding and exercise, termed nabolic resistance (Murton and Greenhaff, 2009; Markofski et al.,

posed model of inflammaging, frailty and sarcopenia. The model describes a central es.

2015; Wall et al., 2015). Moreover, there is little data to suggest that atrogenes or ubiquitin proteasomal degradative pathways are enhanced in older adults, indeed in the fasted state (when pro- tein breakdown is at its highest) there is no difference in protein turnover or signalling through synthetic pathways such as Akt between young and old adults (Francaux et al., 2016).

Anabolic and catabolic pathways may be relevant in periods of extreme inactivity, such as bed rest, and in chronic inflammatory states, such as chronic obstructive pulmonary disease (COPD). In a recent 5 day bed rest study in well characterised healthy young and old subjects, leg lean mass and strength were reduced only in the old subjects. Both subject groups had blunted mTORC1 sig- nalling and increased MURF1 expression in skeletal muscle after bed rest, but only the older group had reduced amino acid induced protein synthetic rates and increased atrogene expression (Tanner et al., 2015). A study investigating the effect of resistance train- ing in participants with COPD, a chronic inflammatory condition, demonstrated higher levels of MAFbx and MURF1 protein expres- sion (atrogenes) and increased phosphorylation of p70s kinases (Constantin et al., 2013). These studies suggest a decrease in mus- cle synthesis and an increase in muscle degradation (dysregulated muscle homeostasis) is seen with inactivity and chronic inflamma- tory conditions.

Patients with sepsis are subject to both periods of extreme inactivity and a pro-inflammatory state and could therefore be considered a model of accelerated ageing (Singer et al., 2016). Fol- lowing sepsis and admission to critical care 70–100% of patients reported prolonged weakness (Callahan and Supinski, 2009) which

is due both to muscle loss and changes in muscle cell functionality. This group deserves further study for a link between inflammation and sarcopenia.

search

3

n t i t 2 i e w c r

e a c h i t s 1 i o 2 d a s a a a

t s a t 2 t t l i s t s B

a r i

3

a m p

3

i a t i 6 i i

D. Wilson et al. / Ageing Re

. Ageing of the immune system

The decline in immune function with age, termed immunese- escence, is well documented and includes increased susceptibility o infections, reduced vaccination responses in older adults and ncreased risk of chronic inflammatory diseases such as Rheuma- oid Arthritis (Weng, 2006; Shaw et al., 2010; Goronzy and Weyand, 013). The many changes that occur in the components of the

mmune system with age have been reviewed previously (Gruver t al., 2007; Ongradi and Kovesdi, 2010; Shaw et al., 2010) and we ill thus consider only those elements of innate immunity that

ould contribute to frailty and sarcopenia, primarily through their ole in inflammation.

Immunesenescence includes inflammaging, the increased pres- nce of a low-grade chronic systemic pro-inflammatory state with ge (Franceschi et al., 2000; Baylis et al., 2013b). Inflammaging is haracterised by increased levels (typically 2–4 fold those seen in ealthy young subjects), of pro-inflammatory cytokines such as

nterleukin 1�(IL-1�), interleukin 6 (IL-6) and tissue necrosis fac- or alpha (TNF�) as well as c-reactive protein (CRP), and a reduced erum level of anti-inflammatory cytokines including interleukin 0 (IL-10) (Baylis et al., 2013b) and IL-1ra. The factors driving

nflammaging are multiple (Fig. 2) and can include increased output f pro-inflammatory cytokines by resting monocytes (Doyle et al., 010; Jackaman et al., 2013; Pinke et al., 2013), reduced IL-10 pro- uction by regulatory lymphocytes (Duggal et al., 2013), increased diposity leading to production of pro-inflammatory adipokines uch as leptin and reduced anti-inflammatory adipokines such as diponectin (Lutz and Quinn, 2012), reduced physical activity with ge (Woods et al., 2012), and senescent cells which build up with ge and secrete pro-inflammatory cytokines (Coppe et al., 2010).

Neutrophils have a fundamental role in the defence against bac- erial infections and in older adults many aspects of their function uch as phagocytosis, superoxide production, and NET generation re impaired with age (reviewed in Hazeldine and Lord, 2015). In his review we focus on reduced chemotactic ability (Sapey et al., 014). Neutrophils migrate from the blood to a site of infection or issue damage in response to chemoattractants, moving through issue by releasing proteases such as neutrophil elastase at their eading edge and damaging healthy tissue in the process resulting n inflammation (Cepinskas et al., 1999). Our previous work has hown that chemotaxis is reduced in older adults making migra- ion inefficient, leading to greater tissue damage and secondary ystemic inflammation (Niwa et al., 1989; Wenisch et al., 2000; utcher et al., 2001; Hazeldine et al., 2014; Sapey et al., 2014).

Whilst investigation of the role of the immune system in frailty nd sarcopenia lags behind similar research into ageing and age- elated conditions, there is evidence that the immune system, and ts dysregulation, may play a role in both processes.

.1. Role of increased systemic inflammation

Multiple associations have been demonstrated between frailty nd sarcopenia and the individual cytokine components of inflam- aging, though evidence of a causal relationship remains to be

roven.

.1.1. Inflammatory cytokines, IL-6 and TNF˛ The potential role of IL-6 in sarcopenia is complex. This cytokine,

nitially thought to be only produced by immune cells, was eventu- lly identified as being produced by muscle and in this context was ermed a ‘myokine’ (Pedersen and Febbraio, 2008). In uninfected

ndividuals muscle is in fact a major source of circulating IL-6. IL-

expression increases acutely in contracting skeletal muscle and s released following exercise (Steensberg et al., 2000), enhanc- ng muscle metabolism, fatty acid oxidation, and glucose uptake

Reviews 36 (2017) 1–10 5

(Kelly et al., 2009). However, there is increasing evidence that IL-6 can act via the ubiquitin proteasome muscle degradation pathway, with raised systemic IL-6 associated with increased ubiquitin pro- tein and mRNA (DeJong et al., 2005), E3 ligase protein and mRNA (White et al., 2012) and proteasome activity (Ebisui et al., 1995). In addition IL-6 can induce insulin resistance which suppresses Akt-mTOR activity and inhibits muscle synthesis (Febbraio et al., 2004; Franckhauser et al., 2008). Another pro-sarcopenic effect of inflammation is on the generation of cortisol within tissues. Corti- sol is profoundly catabolic and can be synthesised from inactive cortisone in tissues including muscle and bone, by the actions of the enzyme 11�HSD1 (Morgan et al., 2009). 11�HSD1 activity increases with age and is induced by cytokines including TNF� and IL-6 (Tomlinson et al., 2004). The systemic increase in inflammation with age may indirectly impact on muscle turnover via induction of 11�HSD1.

A positive association between chronically raised serum IL-6 and TNF� and frailty has been demonstrated in several epidemi- ological studies (Leng et al., 2002; Walston et al., 2002; Leng et al., 2004). Higher serum levels of IL-6 predict development of sarcope- nia (Payette et al., 2003; Schaap et al., 2006) and increased IL-6 also predicts disability and mortality, recognised outcomes of frailty and sarcopenia (Cesari et al., 2012). In addition, high serum IL-6 and CRP at baseline assessment have been associated with a two to threefold greater risk of losing more than 40% of grip strength over three years (Schaap et al., 2006). Using centenarians as a model for ‘healthy ageing’ has also given some support for a link between IL-6, with frailty and sarcopenia in humans. Specifically, the IL-6 174GG genotype, which is associated with higher plasma levels of IL-6, is under-represented in centenarians (Franceschi and Bonafe, 2003).

However, a major limitation in understanding the role of inflam- mation in sarcopenia is the limited number of studies that have measured inflammatory cytokines, whether at the mRNA or protein level, in human skeletal muscle with age. Two studies comparing healthy young and old males reported 3.3 and 2.8 fold increases in mRNA for IL-1� (Przybyla et al., 2006) and TNF� (Leger et al., 2008) for older men. A study comparing frail older adults, defined by physical function testing, with young subjects reported raised TNF� mRNA and protein in myocytes from the frail subjects. More- over, an exercise intervention in these frail adults reduced TNF� mRNA and protein levels and improved muscle strength (Greiwe et al., 2001). In contrast, three studies have found no differences in skeletal muscle IL-6 mRNA with age (Hamada et al., 2005; Przybyla et al., 2006; Trenerry et al., 2008) and two found no age-related increase in TNF� mRNA in males (Hamada et al., 2005) or females (Raue et al., 2007).

The apparent discrepancies between studies of systemic inflam- mation and sarcopenia may indicate that it is the degree and chronicity of inflammation that dictates the effect on muscle mass, strength and quality. Thus relatively mild levels of inflammation such as those seen with normal ageing or with obesity may not be sufficient to effect loss of muscle mass or strength, but could contribute to sarcopenia by affecting metabolic quality (Murton et al., 2017). When systemic inflammation is more severe and accompanied by inflammation in skeletal muscle itself, as may be seen in frailty (Greiwe et al., 2001), then inflammation may also contribute to loss of muscle mass and strength. In support of this proposal exogenous administration of TNF� to mice causes: (1) anorexia and muscle loss, achieved via several mechanisms including reduced amino acid availability via upregulation of lep- tin (Grunfeld et al., 1996; Sarraf et al., 1997); (2) activation of the transcription factor NF-�B in muscle resulting in myofibre; atro-

phy and activation of the ubiquitin-proteasome pathway (Li and Reid, 2000; Ladner et al., 2003; Cai et al., 2004) and (3) suppression of the Akt-mTOR pathway of protein synthesis (Pijet et al., 2013). In rats, infusion of lipopolysaccharide to mimic sepsis induces a

6 D. Wilson et al. / Ageing Research Reviews 36 (2017) 1–10

F d sarc o es.

s s l d c ( w c w

m c r l f i p a A o b

3

t 2 h a s 2 5 m s fl h

ig. 3. Relationships between dysregulation of PI3k-Akt pathway in neutrophils an f PI3k-Akt pathway within neutrophils and muscle and frailty and sarcopenia stat

ignificant systemic inflammatory response and increased expres- ion of IL-6 and TNF� mRNA in skeletal muscle associated with oss of muscle mass and strength(Crossland et al., 2008). Moreover, ampening of the inflammatory response in muscle, by the con- omitant administration of glucocorticoid, preserved muscle mass Crossland et al., 2010). TNF� directly upregulates the NF�� path- ay via I�� kinase (IKK) and induces MuRF-1 expression which

auses myofibril degradation via the ubiquitin proteasome path- ay (Li and Reid, 2000; Ladner et al., 2003).

Multiple chronic inflammatory conditions are associated with uscle loss either described as sarcopenia or cachexia: can-

er, heart failure, COPD, chronic kidney disease, Crohn’s disease, heumatoid arthritis, HIV (Evans, 2010; Biolo et al., 2014). Muscle oss has been investigated at a cellular level in COPD, and whilst urther research is required to confirm the data, on balance there s an increase in ubiquitin proteasome activity and a decrease in rotein synthesis (Constantin et al., 2013). This suggests that the nabolic and catabolic pathways utilising the intra-cellular PI3K- kt pathway are important in the development and maintenance f sarcopenia in chronic inflammatory states. Similar results have een replicated in other chronic inflammatory conditions.

.1.2. Anti-inflammatory cytokines IL-10, an anti-inflammatory cytokine, declines in the circula-

ion with age in humans (Franceschi et al., 2007; Bartlett et al., 012). The development of an IL-10 homozygous knockout mouse as provided an interesting and informative model of sarcopenia nd frailty as it develops increased muscle weakness and decreased trength with age in comparison to wild type mice (Walston et al., 008). This mouse also has significantly raised levels of IL-6 at 0 weeks of age (Walston et al., 2008). At 92 weeks of age these

ice also show compromised skeletal muscle quality, with reduced

keletal muscle energy metabolism in the form of reduced ATP ux via creatine kinase, and lower free energy released during ATP ydrolysis compared to wild type mice (Akki et al., 2014). These

openia and frailty. Figure depicting proposed relationships between dysregulation

mice also show reduced muscle growth and regeneration after injury (Deng et al., 2012). These data offer one potential explanation for why muscle strength declines more quickly than muscle mass in sarcopenia, however there are currently few reports of associa- tions between IL-10 and frailty or sarcopenia in humans. Only one study has compared IL-10 expression in muscle from young and old subjects and shown a modest increase, 1.4 fold, in IL-10 mRNA in healthy older males (Przybyla et al., 2006) However, an IL-10 polymorphism 1082CC, associated with high serum levels of IL- 10, is over-represented in centenarians, suggesting an association with longevity at least (Franceschi and Bonafe, 2003). It is therefore important now to confirm if IL-10 expression is reduced in skeletal muscle from sarcopenic older adults to provide support for its role in muscle loss and frailty in humans.

There are few studies of other anti-inflammatory cytokines and their expression in skeletal muscle. One study found that interleukin-1 receptor antagonist (IL1-ra) mRNA was increased 7.2 fold in healthy older males in comparison to younger males (Przybyla et al., 2006) but this has not yet been confirmed by oth- ers. The authors suggested this may be a functional response to the elevated IL-1� mRNA also demonstrated in the healthy older males.

Fig. 2 proposes a relationship between inflammaging, sarcope- nia and frailty, representing a coalescence of ideas that may underpin the potential relationship between inflammaging and sarcopenia. At present mechanistic insight cannot be given as fur- ther research is required, especially in humans and evidence of a direct causal relationship is thus also missing.

3.1.3. Leukocytes, sarcopenia and frailty Age-related changes to the cells of the innate immune system

may contribute indirectly to frailty and sarcopenia via their role

in the age-related increase in systemic inflammation. White cell counts and neutrophil numbers after adjustment for the most com- mon confounders are raised in populations of frail older people (Leng et al., 2007; Leng et al., 2009; Collerton et al., 2012). Higher

search

n i c ( s i

w w p t e 2 i N s a ( H h w d s s v I i d

u I n r o i d A a m

c p ( 2 i s n m t n

4

e d h c r c s t a m F

D. Wilson et al. / Ageing Re

eutrophil counts are associated with low levels of physical activ- ty and frailty (Fernandez-Garrido et al., 2014) and a higher white ell count in healthy 60 year olds can predict frailty ten years later Baylis et al., 2013a). How such changes might affect frailty and arcopenia is still poorly understood but we attempt to offer some nsight here.

Neutrophils are the most abundant leukocyte in the blood and e have shown that their chemotactic ability is greatly reduced ith age. Consequently migration is inefficient, the neutrophils roduce more tissue damage and secondary systemic inflamma- ion as they migrate through tissue (Niwa et al., 1989; Wenisch t al., 2000; Butcher et al., 2001; Hazeldine et al., 2014; Sapey et al., 014). Therefore it is plausible that neutrophils play a key role

n the inflammatory mechanisms seen in sarcopenia and frailty. eutrophils are central to tissue repair and research has demon-

trated in a number of models of muscle injury that neutrophils re recruited to the site of the injury within a couple of hours Smith et al., 1998; MacIntyre et al., 2000; Quindry et al., 2003). owever, migrating neutrophils also cause secondary damage to ealthy muscle and studies report that muscle damage is reduced hen functioning neutrophils are prevented from migrating to the amaged tissue (Jolly et al., 1986; Korthuis et al., 1988). The original tudies used an ischaemia and reperfusion model but subsequent tudies have utilised a muscle stretch injury model and directly isualised the muscle damage by microscopy (Brickson et al., 2003). nefficient neutrophil migration may thus be a major contributor to ncreased inflammation in older adults especially at times of muscle amage (Fig. 3).

Recent data from our group has identified the mechanism nderlying reduced chemotaxis in neutrophils from old donors.

naccurate chemotaxis was associated with constitutive PI3K sig- alling and selective pharmacological inhibition of PI3K� or PI3K� estored neutrophil migratory accuracy (Sapey et al., 2014). More- ver, the reduced neutrophil chemotaxis was associated with ncreased systemic inflammation in the older donors, most likely ue to the tissue damage that occurs during neutrophil migration. s there are inhibitors of PI3K� currently in clinical trial, this offers

novel route to therapy for immunesenescence and in theory this ay also improve frailty and sarcopenia states. As muscle ages it becomes more susceptible to injury and

ertainly as a person ages dysregulation of entire systems, for exam- le balance and cognition, result in a greater number of injuries Campbell et al., 1981; van Doorn et al., 2003; Shavlakadze et al., 010; Shubert, 2011). It can be postulated that muscle injury

n an older person combined with immune ageing would cause econdary damage to healthy muscle from aberrantly migrating eutrophils resulting in myocyte damage and apoptosis and loss of uscle fibres. This loss of muscle quality and mass could result in

he functional losses and physical weakness of frailty. Research is ow required to acquire evidence to test this hypothesis.

. Conclusions

The historical difficulties of definition, measurement and mod- lling in both sarcopenia and frailty in addition to the fundamental ifficulties of investigating complex, multi-factorial syndromes as led to a lack of information regarding the pathophysiologi- al causes of frailty and sarcopenia. Whilst there is some limited esearch into associations there is very little investigating more omplex pathways attempting to link the two syndromes. The uggested link of increased systemic inflammation could explain

he relationship between sarcopenia and immunesenescence, with berrant neutrophil migration potentially contributing to inflam- aging and tissue damage associated with sarcopenia and frailty.

urther research on the cell pathways connecting inflammaging,

Reviews 36 (2017) 1–10 7

sarcopenia and frailty would help to better understand these con- ditions and progress to potential novel therapies for frailty and sarcopenia which could include modulation of PI3k to correct neu- trophil chemotaxis.

Acknowledgments

Daisy Wilson is supported by a clinical research fellowship funded by the MRC-Arthritis Research UK Centre for Musculoskele- tal Ageing Research. Elizabeth Sapey is funded by the Medical Research Council.

We would like to thank Professor Paul Greenhaff for his careful reading of the manuscript.

We would also like to thank Alexandria Clark for her work in improving the visual appearance of the figures.

References

Akki, A., Yang, H., Gupta, A., Chacko, V.P., Yano, T., Leppo, M.K., Steenbergen, C., Walston, J., Weiss, R.G., 2014. Skeletal muscle ATP kinetics are impaired in frail mice. Age (Dordr) 36, 21–30.

Bartlett, D.B., Firth, C.M., Phillips, A.C., Moss, P., Baylis, D., Syddall, H., Sayer, A.A., Cooper, C., Lord, J.M., 2012. The age-related increase in low-grade systemic inflammation (Inflammaging) is not driven by cytomegalovirus infection. Aging Cell 11, 912–915.

Baumgartner, R.N., Koehler, K.M., Gallagher, D., Romero, L., Heymsfield, S.B., Ross, R.R., Garry, P.J., Lindeman, R.D., 1998. Epidemiology of sarcopenia among the elderly in New Mexico. Am. J. Epidemiol. 147, 755–763.

Baylis, D., Bartlett, D., Syddall, H., Ntani, G., Gale, C., Cooper, C., Lord, J., Sayer, A., 2013a. Immune-endocrine biomarkers as predictors of frailty and mortality: a 10-year longitudinal study in community-dwelling older people. Age 35, 963–971.

Baylis, D., Bartlett, D.B., Patel, H.P., Roberts, H.C., 2013b. Understanding how we age: insights into inflammaging. Longev. Healthspan 2, 1–8.

Biolo, G., Cederholm, T., Muscaritoli, M., 2014. Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia. Clin. Nutr. 33, 737–748.

Bouillon, K., Kivimaki, M., Hamer, M., Sabia, S., Fransson, E.I., Singh-Manoux, A., Gale, C.R., Batty, G.D., 2013. Measures of frailty in population-based studies: an overview. BMC Geriatr. 13, 64.

Brickson, S., Ji, L.L., Schell, K., Olabisi, R., St Pierre Schneider, B., Best, T.M., 2003. M1/70 attenuates blood-borne neutrophil oxidants, activation, and myofiber damage following stretch injury. J. Appl. Physiol. (1985) 95, 969–976.

Butcher, S.K., Chahal, H., Nayak, L., Sinclair, A., Henriquez, N.V., Sapey, E., O’Mahony, D., Lord, J.M., 2001. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J. Leukoc. Biol. 70, 881–886.

Cai, D., Frantz, J.D., Tawa Jr., N.E., Melendez, P.A., Oh, B.C., Lidov, H.G., Hasselgren, P.O., Frontera, W.R., Lee, J., Glass, D.J., Shoelson, S.E., 2004. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119, 285–298.

Callahan, L.A., Supinski, G.S., 2009. Sepsis-induced myopathy. Crit. Care Med. 37, S354–367.

Cameron, I.D., Fairhall, N., Langron, C., Lockwood, K., Monaghan, N., Aggar, C., Sherrington, C., Lord, S.R., Kurrle, S.E., 2013. A multifactorial interdisciplinary intervention reduces frailty in older people: randomized trial. BMC Med. 11, 65.

Campbell, A.J., Reinken, J., Allan, B.C., Martinez, G.S., 1981. Falls in old age: a study of frequency and related clinical factors. Age Ageing 10, 264–270.

Cawthon, P.M., Marshall, L.M., Michael, Y., Dam, T.T., Ensrud, K.E., Barrett-Connor, E., Orwoll, E.S., Osteoporotic Fractures in Men Research Group, 2007. Frailty in older men: prevalence, progression, and relationship with mortality. J. Am. Geriatr. Soc. 55, 1216–1223.

Cepinskas, G., Sandig, M., Kvietys, P.R., 1999. PAF-induced elastase-dependent neutrophil transendothelial migration is associated with the mobilization of elastase to the neutrophil surface and localization to the migrating front. J. Cell Sci. 112 (Pt. 12), 1937–1945.

Cesari, M., Kritchevsky, S.B., Nicklas, B., Kanaya, A.M., Patrignani, P., Tacconelli, S., Tranah, G.J., Tognoni, G., Harris, T.B., Incalzi, R.A., Newman, A.B., Pahor, M., 2012. Oxidative damage, platelet activation, and inflammation to predict mobility disability and mortality in older persons: results from the health aging and body composition study. J. Gerontol. A: Biol. Sci. Med. Sci. 67, 671–676.

Chien, M.Y., Huang, T.Y., Wu, Y.T., 2008. Prevalence of sarcopenia estimated using a bioelectrical impedance analysis prediction equation in community-dwelling elderly people in Taiwan. J. Am. Geriatr. Soc. 56, 1710–1715.

Collard, R.M., Boter, H., Schoevers, R.A., Oude Voshaar, R.C., 2012. Prevalence of frailty in community-dwelling older persons: a systematic review. J. Am.

Geriatr. Soc. 60, 1487–1492.

Collerton, J., Martin-Ruiz, C., Davies, K., Hilkens, C.M., Isaacs, J., Kolenda, C., Parker, C., Dunn, M., Catt, M., Jagger, C., 2012. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study. Mech. Ageing Dev. 133, 456–466.

8 search

C

C

C

C

C

C

D

D

D

D

E

E

E

F

F

F

F

F

F

F

F

F

F

F

D. Wilson et al. / Ageing Re

onstantin, D., Menon, M.K., Houchen-Wolloff, L., Morgan, M.D., Singh, S.J., Greenhaff, P., Steiner, M.C., 2013. Skeletal muscle molecular responses to resistance training and dietary supplementation in COPD. Thorax 68, 625–633.

oppe, J.P., Desprez, P.Y., Krtolica, A., Campisi, J., 2010. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118.

rossland, H., Constantin-Teodosiu, D., Gardiner, S.M., Constantin, D., Greenhaff, P.L., 2008. A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle. J. Physiol. London 586, 5589–5600.

rossland, H., Constantin-Teodosiu, D., Greenhaff, P.L., Gardiner, S.M., 2010. Low-dose dexamethasone prevents endotoxaemia-induced muscle protein loss and impairment of carbohydrate oxidation in rat skeletal muscle. J. Physiol. London 588, 1333–1347.

ruz-Jentoft, A.J., Baeyens, J.P., Bauer, J.M., Boirie, Y., Cederholm, T., Landi, F., Martin, F.C., Michel, J.P., Rolland, Y., Schneider, S.M., Topinkova, E., Vandewoude, M., Zamboni, M., 2010a. Sarcopenia: European consensus on definition and diagnosis: report of the european working group on sarcopenia in older people. Age Ageing 39, 412–423.

ruz-Jentoft, A.J., Baeyens, J.P., Bauer, J.M., Boirie, Y., Cederholm, T., Landi, F., Martin, F.C., Michel, J.P., Rolland, Y., Schneider, S.M., Topinkova, E., Vandewoude, M., Zamboni, M., European Working Group on Sarcopenia in Older People, 2010b. Sarcopenia: European consensus on definition and diagnosis: report of the european working group on sarcopenia in older people. Age Ageing 39, 412–423.

eJong, C.H., Busquets, S., Moses, A.G., Schrauwen, P., Ross, J.A., Argiles, J.M., Fearon, K.C., 2005. Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia. Oncol. Rep. 14, 257–263.

eng, B., Wehling-Henricks, M., Villalta, S.A., Wang, Y., Tidball, J.G., 2012. IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J. Immunol. 189, 3669–3680.

oyle, K.P., Cekanaviciute, E., Mamer, L.E., Buckwalter, M.S., 2010. TGFbeta signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke. J. Neuroinflammation 7, 62.

uggal, N.A., Upton, J., Phillips, A.C., Sapey, E., Lord, J.M., 2013. An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity. Aging Cell 12, 873–881.

bisui, C., Tsujinaka, T., Morimoto, T., Kan, K., Iijima, S., Yano, M., Kominami, E., Tanaka, K., Monden, M., 1995. Interleukin-6 induces proteolysis by activating intracellular proteases (cathepsins B and L: proteasome) in C2C12 myotubes. Clin. Sci. (Lond.) 89, 431–439.

spinoza, S.E., Jung, I., Hazuda, H., 2012. Frailty transitions in the San Antonio Longitudinal Study of Aging. J. Am. Geriatr. Soc. 60, 652–660.

vans, W.J., 2010. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am. J. Clin. Nutr. 91, 1123S–1127S.

allah, N., Mitnitski, A., Searle, S.D., Gahbauer, E.A., Gill, T.M., Rockwood, K., 2011. Transitions in frailty status in older adults in relation to mobility: a multistate modeling approach employing a deficit count. J. Am. Geriatr. Soc. 59, 524–529.

ebbraio, M.A., Hiscock, N., Sacchetti, M., Fischer, C.P., Pedersen, B.K., 2004. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53, 1643–1648.

ernandez-Garrido, J., Navarro-Martinez, R., Buigues-Gonzalez, C., Martinez-Martinez, M., Ruiz-Ros, V., Cauli, O., 2014. The value of neutrophil and lymphocyte count in frail older women. Exp. Gerontol. 54, 35–41.

iatarone, M.A., O’Neill, E.F., Ryan, N.D., Clements, K.M., Solares, G.R., Nelson, M.E., Roberts, S.B., Kehayias, J.J., Lipsitz, L.A., Evans, W.J., 1994. Exercise training and nutritional supplementation for physical frailty in very elderly people. N. Engl. J. Med. 330, 1769–1775.

rancaux, M., Demeulder, B., Naslain, D., Fortin, R., Lutz, O., Caty, G., Deldicque, L., 2016. Aging reduces the activation of the mTORC1 pathway after resistance exercise and protein intake in human skeletal muscle: potential role of REDD1 and impaired anabolic sensitivity. Nutrients 8.

ranceschi, C., Bonafe, M., 2003. Centenarians as a model for healthy aging. Biochem. Soc. Trans. 31, 457–461.

ranceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., De Benedictis, G., 2000. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254.

ranceschi, C., Capri, M., Monti, D., Giunta, S., Olivieri, F., Sevini, F., Panouraia, M.P., Invidia, L., Celani, L., Scurti, M., Cevenini, E., Castellani, G.C., Salvioli, S., 2007. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92–105.

ranckhauser, S., Elias, I., Rotter Sopasakis, V., Ferre, T., Nagaev, I., Andersson, C.X., Agudo, J., Ruberte, J., Bosch, F., Smith, U., 2008. Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 51, 1306–1316.

ried, L.P., Tangen, C.M., Walston, J., Newman, A.B., Hirsch, C., Gottdiener, J., Seeman, T., Tracy, R., Kop, W.J., Burke, G., 2001. Frailty in older adults evidence for a phenotype. J. Gerontol.Ser.A: Biol. Sci. Med. Sci. 56, M146–M157.

ried, L.P., Xue, Q.L., Cappola, A.R., Ferrucci, L., Chaves, P., Varadhan, R., Guralnik, J.M., Leng, S.X., Semba, R.D., Walston, J.D., Blaum, C.S., Bandeen-Roche, K., 2009.

Nonlinear multisystem physiological dysregulation associated with frailty in older women: implications for etiology and treatment. J. Gerontol. A: Biol. Sci. Med. Sci. 64, 1049–1057.

Reviews 36 (2017) 1–10

Gill, T.M., Gahbauer, E.A., Allore, H.G., Han, L., 2006. Transitions between frailty states among community-living older persons. Arch. Intern. Med. 166, 418–423.

Goodpaster, B.H., Park, S.W., Harris, T.B., Kritchevsky, S.B., Nevitt, M., Schwartz, A.V., Simonsick, E.M., Tylavsky, F.A., Visser, M., Newman, A.B., 2006. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J. Gerontol. A: Biol. Sci. Med. Sci. 61, 1059–1064.

Goronzy, J.J., Weyand, C.M., 2013. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 14, 428–436.

Greiwe, J.S., Cheng, B., Rubin, D.C., Yarasheski, K.E., Semenkovich, C.F., 2001. Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J. 15, 475–482.

Grunfeld, C., Zhao, C., Fuller, J., Pollack, A., Moser, A., Friedman, J., Feingold, K.R., 1996. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J. Clin. Invest. 97, 2152–2157.

Gruver, A.L., Hudson, L.L., Sempowski, G.D., 2007. Immunosenescence of ageing. J. Pathol. 211, 144–156.

Hamada, K., Vannier, E., Sacheck, J.M., Witsell, A.L., Roubenoff, R., 2005. Senescence of human skeletal muscle impairs the local inflammatory cytokine response to acute eccentric exercise. FASEB J. 19, 264–266.

Harrington, L.S., Findlay, G.M., Gray, A., Tolkacheva, T., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N.R., Cheng, S., Shepherd, P.R., Gout, I., Downes, C.P., Lamb, R.F., 2004. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213–223.

Hazeldine, J., Harris, P., Chapple, I.L., Grant, M., Greenwood, H., Livesey, A., Sapey, E., Lord, J.M., 2014. Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals. Aging Cell 13, 690–698.

Hazeldine, J., Lord, J.M., 2015. Innate immunesenescence: underlying mechanisms an clinical relevance. Biogerentology 16 (2April (2)), 187–201.

Huang, H., Tindall, D.J., 2007. Dynamic FoxO transcription factors. J. Cell Sci. 120, 2479–2487.

Jackaman, C., Radley-Crabb, H.G., Soffe, Z., Shavlakadze, T., Grounds, M.D., Nelson, D.J., 2013. Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice. Aging Cell 12, 345–357.

Jang, S.W., Yang, S.J., Srinivasan, S., Ye, K., 2007. Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. J. Biol. Chem. 282, 30836–30844.

Jolly, S.R., Kane, W.J., Hook, B.G., Abrams, G.D., Kunkel, S.L., Lucchesi, B.R., 1986. Reduction of myocardial infarct size by neutrophil depletion: effect of duration of occlusion. Am. Heart J. 112, 682–690.

Kelly, M., Gauthier, M.S., Saha, A.K., Ruderman, N.B., 2009. Activation of AMP-activated protein kinase by interleukin-6 in rat skeletal muscle association with changes in cAMP, energy state, and endogenous fuel mobilization. Diabetes 58, 1953–1960.

Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T.P., Guan, K.L., 2008. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945.

Kline, W.O., Panaro, F.J., Yang, H., Bodine, S.C., 2007. Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol. J. Appl. Physiol. (1985) 102, 740–747.

Korthuis, R.J., Grisham, M.B., Granger, D.N., 1988. Leukocyte depletion attenuates vascular injury in postischemic skeletal muscle. Am. J. Physiol. 254, H823–827.

Ladner, K.J., Caligiuri, M.A., Guttridge, D.C., 2003. Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for cytokine-induced loss of skeletal muscle gene products. J. Biol. Chem. 278, 2294–2303.

Landi, F., Liperoti, R., Fusco, D., Mastropaolo, S., Quattrociocchi, D., Proia, A., Russo, A., Bernabei, R., Onder, G., 2012. Prevalence and risk factors of sarcopenia among nursing home older residents. J. Gerontol. A: Biol. Sci. Med. Sci. 67, 48–55.

Lee, J.S., Auyeung, T.W., Leung, J., Kwok, T., Woo, J., 2014. Transitions in frailty states among community-living older adults and their associated factors. J. Am. Med. Dir. Assoc. 15, 281–286.

Leger, B., Derave, W., De Bock, K., Flespel, P., Russell, A.P., 2008. Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of akt phosphorylation. Rejuvenation Res. 11, 163–175.

Leng, S., Chaves, P., Koenig, K., Walston, J., 2002. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J. Am. Geriatr. Soc. 50, 1268–1271.

Leng, S.X., Cappola, A.R., Andersen, R.E., Blackman, M.R., Koenig, K., Blair, M., Walston, J.D., 2004. Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty. Aging Clin. Exp. Res. 16, 153–157.

Leng, S.X., Xue, Q.L., Tian, J., Walston, J.D., Fried, L.P., 2007. Inflammation and frailty in older women. J. Am. Geriatr. Soc. 55, 864–871.

Leng, S.X., Xue, Q.-L., Tian, J., Huang, Y., Yeh, S.-H., Fried, L.P., 2009. Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: results from the Women’s Health and Aging Studies I. Exp. Gerontol. 44, 511–516.

Li, Y.P., Reid, M.B., 2000. NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes. Am. J. Physiol. Regul.

Integr. Comp. Physiol. 279, R1165–1170.

Liu-Ambrose, T., Khan, K.M., Eng, J.J., Janssen, P.A., Lord, S.R., McKay, H.A., 2004. Resistance and agility training reduce fall risk in women aged 75 to 85 with low bone mass: a 6-month randomized, controlled trial. J. Am. Geriatr. Soc. 52, 657–665.

search

L

M

M

M

M

M

M

M

M

M

N

N

N

O

P

P

P

P

P

P

P

Q

R

R

R

R

D. Wilson et al. / Ageing Re

utz, C.T., Quinn, L.S., 2012. Sarcopenia, obesity, and natural killer cell immune senescence in aging: altered cytokine levels as a common mechanism. Aging (Milano) 4, 535–546.

acIntyre, D.L., Reid, W.D., Lyster, D.M., McKenzie, D.C., 2000. Different effects of strenuous eccentric exercise on the accumulation of neutrophils in muscle in women and men. Eur. J. Appl. Physiol. 81, 47–53.

arkofski, M.M., Dickinson, J.M., Drummond, M.J., Fry, C.S., Fujita, S., Gundermann, D.M., Glynn, E.L., Jennings, K., Paddon-Jones, D., Reidy, P.T., Sheffield-Moore, M., Timmerman, K.L., Rasmussen, B.B., Volpi, E., 2015. Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women. Exp. Gerontol. 65, 1–7.

cFarlane, C., Plummer, E., Thomas, M., Hennebry, A., Ashby, M., Ling, N., Smith, H., Sharma, M., Kambadur, R., 2006. Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism. J. Cell. Physiol. 209, 501–514.

etzelthin, S.F., Daniels, R., van Rossum, E., de Witte, L., van den Heuvel, W.J., Kempen, G.I., 2010. The psychometric properties of three self-report screening instruments for identifying frail older people in the community. BMC Public Health 10, 176.

itnitski, A.B., Mogilner, A.J., Rockwood, K., 2001. Accumulation of deficits as a proxy measure of aging. Sci. World J. 1, 323–336.

organ, S.A., Sherlock, M., Gathercole, L.L., Lavery, G.G., Lenaghan, C., Bujalska, I.J., Laber, D., Yu, A., Convey, G., Mayers, R., Hegyi, K., Sethi, J.K., Stewart, P.M., Smith, D.M., Tomlinson, J.W., 2009. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle. Diabetes 58, 2506–2515.

orley, J.E., Vellas, B., van Kan, G.A., Anker, S.D., Bauer, J.M., Bernabei, R., Cesari, M., Chumlea, W.C., Doehner, W., Evans, J., Fried, L.P., Guralnik, J.M., Katz, P.R., Malmstrom, T.K., McCarter, R.J., Gutierrez Robledo, L.M., Rockwood, K., von Haehling, S., Vandewoude, M.F., Walston, J., 2013. Frailty consensus: a call to action. J. Am. Med. Dir. Assoc. 14, 392–397.

urton, A.J., Greenhaff, P.L., 2009. Muscle atrophy in immobilization and senescence in humans. Curr. Opin. Neurol. 22, 500–505.

urton, A.J., Maddocks, M., Stephens, F.B., Marimuthu, K., England, R., Wilcock, A., 2017. Consequences of late stage non-small cell lung cancer cachexia on muscle metabolic processes. Clin Lung Cancer. 18 (1), e1–e11.

arici, M.V., Maffulli, N., 2010. Sarcopenia: characteristics, mechanisms and functional significance. Br. Med. Bull. 95, 139–159.

ewman, A.B., Kupelian, V., Visser, M., Simonsick, E., Goodpaster, B., Nevitt, M., Kritchevsky, S.B., Tylavsky, F.A., Rubin, S.M., Harris, T.B., Health, A.B.C.S.I., 2003. Sarcopenia: alternative definitions and associations with lower extremity function. J. Am. Geriatr. Soc. 51, 1602–1609.

iwa, Y., Kasama, T., Miyachi, Y., Kanoh, T., 1989. Neutrophil chemotaxis, phagocytosis and parameters of reactive oxygen species in human aging: cross-sectional and longitudinal studies. Life Sci. 44, 1655–1664.

ngradi, J., Kovesdi, V., 2010. Factors that may impact on immunosenescence: an appraisal. Immun. Ageing 7, 7.

atel, H.P., Al-Shanti, N., Davies, L.C., Barton, S.J., Grounds, M.D., Tellam, R.L., Stewart, C.E., Cooper, C., Sayer, A.A., 2014. Lean mass, muscle strength and gene expression in community dwelling older men: findings from the Hertfordshire Sarcopenia Study (HSS). Calcif. Tissue Int. 95, 308–316.

ayette, H., Roubenoff, R., Jacques, P.F., Dinarello, C.A., Wilson, P.W., Abad, L.W., Harris, T., 2003. Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: the Framingham Heart Study. J. Am. Geriatr. Soc. 51, 1237–1243.

edersen, B.K., Febbraio, M.A., 2008. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379–1406.

ijet, B., Pijet, M., Litwiniuk, A., Gajewska, M., Pajak, B., Orzechowski, A., 2013. TNF- alpha and IFN-s-dependent muscle decay is linked to NF-kappaB- and STAT-1alpha-stimulated Atrogin1 and MuRF1 genes in C2C12 myotubes. Mediators Inflamm. 2013, 171437.

inke, K.H., Calzavara, B., Faria, P.F., do Nascimento, M.P., Venturini, J., Lara, V.S., 2013. Proinflammatory profile of in vitro monocytes in the ageing is affected by lymphocytes presence. Immun. Ageing 10, 22.

olager, S., Ofir, M., Ginsberg, D., 2008. E2F1 regulates autophagy and the transcription of autophagy genes. Oncogene 27, 4860–4864.

rzybyla, B., Gurley, C., Harvey, J.F., Bearden, E., Kortebein, P., Evans, W.J., Sullivan, D.H., Peterson, C.A., Dennis, R.A., 2006. Aging alters macrophage properties in human skeletal muscle both at rest and in response to acute resistance exercise. Exp. Gerontol. 41, 320–327.

uindry, J.C., Stone, W.L., King, J., Broeder, C.E., 2003. The effects of acute exercise on neutrophils and plasma oxidative stress. Med. Sci. Sports Exerc. 35, 1139–1145.

aiche, M., Hebert, R., Dubois, M.F., 2008. PRISMA-7: a case-finding tool to identify older adults with moderate to severe disabilities. Arch. Gerontol. Geriatr. 47, 9–18.

aue, U., Slivka, D., Jemiolo, B., Hollon, C., Trappe, S., 2007. Proteolytic gene expression differs at rest and after resistance exercise between young and old women. J. Gerontol. A: Biol. 62, 1407–1412.

eijnierse, E.M., Trappenburg, M.C., Blauw, G.J., Verlaan, S., de van der Schueren, M.A., Meskers, C.G., Maier, A.B., 2016. Common ground? The concordance of

sarcopenia and frailty definitions. J. Am. Med. Dir. Assoc. 17 (371), e377-371 e312.

ockwood, K., Andrew, M., Mitnitski, A., 2007. A comparison of two approaches to measuring frailty in elderly people. J. Gerontol. Ser. A: Biol. Sci. Med. Sci. 62, 738–743.

Reviews 36 (2017) 1–10 9

Rolfson, D.B., Majumdar, S.R., Tsuyuki, R.T., Tahir, A., Rockwood, K., 2006. Validity and reliability of the edmonton frail scale. Age Ageing 35, 526–529.

Rothman, M.D., Leo-Summers, L., Gill, T.M., 2008. Prognostic significance of potential frailty criteria. J. Am. Geriatr. Soc. 56, 2211–2216.

Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar-Peled, L., Sabatini, D.M., 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501.

Sapey, E., Greenwood, H., Walton, G., Mann, E., Love, A., Aaronson, N., Insall, R.H., Stockley, R.A., Lord, J.M., 2014. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 123, 239–248.

Sarbassov, D.D., Guertin, D.A., Ali, S.M., Sabatini, D.M., 2005. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101.

Sarraf, P., Frederich, R.C., Turner, E.M., Ma, G., Jaskowiak, N.T., Rivet 3rd, D.J., Flier, J.S., Lowell, B.B., Fraker, D.L., Alexander, H.R., 1997. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J. Exp. Med. 185, 171–175.

Schaap, L.A., Pluijm, S.M., Deeg, D.J., Visser, M., 2006. Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am. J. Med. 119 (52), e529–517.

Schiaffino, S., Mammucari, C., 2011. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet Muscle 1, 4.

Shavlakadze, T., McGeachie, J., Grounds, M.D., 2010. Delayed but excellent myogenic stem cell response of regenerating geriatric skeletal muscles in mice. Biogerontology 11, 363–376.

Shaw, A.C., Joshi, S., Greenwood, H., Panda, A., Lord, J.M., 2010. Aging of the innate immune system. Curr. Opin. Immunol. 22, 507–513.

Shubert, T.E., 2011. Evidence-based exercise prescription for balance and falls prevention: a current review of the literature. J. Geriatr. Phys. Ther. 34, 100–108.

Singer, M., Deutschman, C.S., Seymour, C.W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G.R., Chiche, J.D., Coopersmith, C.M., Hotchkiss, R.S., Levy, M.M., Marshall, J.C., Martin, G.S., Opal, S.M., Rubenfeld, G.D., van der Poll, T., Vincent, J.L., Angus, D.C., 2016. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA J. Am. Med. Assoc. 315, 801–810.

Smith, L.L., Bond, J.A., Holbert, D., Houmard, J.A., Israel, R.G., McCammon, M.R., Smith, S.S., 1998. Differential white cell count after two bouts of downhill running. Int. J. Sports Med. 19, 432–437.

Song, X., Mitnitski, A., Rockwood, K., 2010. Prevalence and 10-Year outcomes of frailty in older adults in relation to deficit accumulation. J. Am. Geriatr. Soc. 58, 681–687.

Steensberg, A., van Hall, G., Osada, T., Sacchetti, M., Saltin, B., Pedersen, B.K., 2000. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J. Physiol. London 529, 237–242.

Stitt, T.N., Drujan, D., Clarke, B.A., Panaro, F., Timofeyva, Y., Kline, W.O., Gonzalez, M., Yancopoulos, G.D., Glass, D.J., 2004. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol. Cell 14, 395–403.

Suzuki, N., Motohashi, N., Uezumi, A., Fukada, S., Yoshimura, T., Itoyama, Y., Aoki, M., Miyagoe-Suzuki, Y., Takeda, S., 2007. NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS. J. Clin. Invest. 117, 2468–2476.

Tanner, R.E., Brunker, L.B., Agergaard, J., Barrows, K.M., Briggs, R.A., Kwon, O.S., Young, L.M., Hopkins, P.N., Volpi, E., Marcus, R.L., LaStayo, P.C., Drummond, M.J., 2015. Age-related differences in lean mass, protein synthesis and skeletal muscle markers of proteolysis after bed rest and exercise rehabilitation. J. Physiol. London 593, 4259–4273.

Tomlinson, J.W., Walker, E.A., Bujalska, I.J., Draper, N., Lavery, G.G., Cooper, M.S., Hewison, M., Stewart, P.M., 2004. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr. Rev. 25, 831–866.

Trenerry, M.K., Carey, K.A., Ward, A.C., Farnfield, M.M., Cameron-Smith, D., 2008. Exercise-induced activation of STAT3 signaling is increased with age. Rejuvenation Res. 11, 717–724.

van Doorn, C., Gruber-Baldini, A.L., Zimmerman, S., Hebel, J.R., Port, C.L., Baumgarten, M., Quinn, C.C., Taler, G., May, C., Magaziner, J., 2003. Dementia as a risk factor for falls and fall injuries among nursing home residents. J. Am. Geriatr. Soc. 51, 1213–1218.

von Haehling, S., Morley, J.E., Anker, S.D., 2010. An overview of sarcopenia: facts and numbers on prevalence and clinical impact. J. Cachexia Sarcopenia Muscle 1, 129–133.

von Maltzahn, J., Bentzinger, C.F., Rudnicki, M.A., 2012. Wnt7a-Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle. Nat. Cell Biol. 14, 186–191.

Wall, B.T., Gorissen, S.H., Pennings, B., Koopman, R., Groen, B.B.L., Verdijk, L.B., van Loon, L.J.C., 2015. Aging is accompanied by a blunted muscle protein synthetic response to protein ingestion. PLoS One 10.

Walston, J., McBurnie, M.A., Newman, A., Tracy, R.P., Kop, W.J., Hirsch, C.H., Gottdiener, J., Fried, L.P., 2002. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. Arch. Intern. Med. 162, 2333–2341.

Walston, J., Fedarko, N., Yang, H., Leng, S., Beamer, B., Espinoza, S., Lipton, A., Zheng, H., Becker, K., 2008. The physical and biological characterization of a frail mouse model. J. Gerontol. A: Biol. Sci. Med. Sci. 63, 391–398.

Weng, N.P., 2006. Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24, 495–499.

1 search

W

W

W

and aging. Aging Dis. 3, 130–140. Xue, Q.L., Bandeen-Roche, K., Varadhan, R., Zhou, J., Fried, L.P., 2008. Initial

manifestations of frailty criteria and the development of frailty phenotype in

0 D. Wilson et al. / Ageing Re

enisch, C., Patruta, S., Daxbock, F., Krause, R., Horl, W., 2000. Effect of age on human neutrophil function. J. Leukoc. Biol. 67, 40–45.

hite, J.P., Puppa, M.J., Sato, S., Gao, S., Price, R.L., Baynes, J.W., Kostek, M.C., Matesic, L.E., Carson, J.A., 2012. IL-6 regulation on skeletal muscle

mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse. Skelet Muscle 2, 14.

illiamson, D.L., Raue, U., Slivka, D.R., Trappe, S., 2010. Resistance exercise, skeletal muscle FOXO3A, and 85-year-old women. J. Gerontol. A: Biol. Sci. Med. Sci. 65, 335–343.

Reviews 36 (2017) 1–10

Woods, J.A., Wilund, K.R., Martin, S.A., Kistler, B.M., 2012. Exercise, inflammation

the Women’s Health and Aging Study II. J. Gerontol. A: Biol. Sci. Med. Sci. 63, 984–990.

  • Frailty and sarcopenia: The potential role of an aged immune system
    • 1 Introduction
      • 1.1 Frailty
      • 1.2 Sarcopenia
      • 1.3 Relationships between frailty and sarcopenia
    • 2 Pathophysiology of sarcopenia and frailty
      • 2.1 Regulation of muscle mass
    • 3 Ageing of the immune system
      • 3.1 Role of increased systemic inflammation
        • 3.1.1 Inflammatory cytokines, IL-6 and TNFα
        • 3.1.2 Anti-inflammatory cytokines
        • 3.1.3 Leukocytes, sarcopenia and frailty
    • 4 Conclusions
    • Acknowledgments
    • References