Mechanisms of Ageing and Development 222 (2024) 111997

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Mechanisms of Ageing and Development

journal homepage: www.elsevier.com/locate/mechagedev

Deciphering Osteosarcopenia through the hallmarks of aging

Francisca Franulic a,b, Felipe Salech a,b,c,d , Daniel Rivas e, Gustavo Duque e,f,*
a
Sección de Geriatría, Hospital Clínico Universidad de Chile, Santiago de Chile, Chile
b
Centro de Investigación Clínica Avanzada (CICA), Hospital Clínico Universidad de Chile, Santiago de Chile, Chile
c
Ageing and Quality of life Nucleus, INTA, Universidad de Chile, Santiago de Chile, Chile
d
Centre FONDAP for Aging, Brain and Metabolism GERO, Universidad de Chile, Santiago de Chile, Chile
e
Bone, Muscle & Geroscience Group, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
f
Dr Joseph Kaufmann Chair in Geriatric Medicine, Department of Medicine, McGill University, Montreal, QC, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Osteosarcopenia is a major driver of functional loss and a risk factor for falls, fractures, disability and mortality in
Geroscience older adults, urgently requiring the development of effective interventions to address it. The hallmarks of aging
Bone provide a theoretical and practical framework that allows for the structured organization of current knowledge
Muscle
and the planning of new development lines. This article comprehensively reviews the currently available liter­
Aging
ature on the role of the hallmarks of aging in the development of osteosarcopenia, thereby offering a panoramic
Osteosarcopenia
Sarcopenia view of the state of the art and knowledge gaps in this field.
Osteoporosis

1. Introduction density and quality, muscle mass, and strength (Berger et al., 2008;
Janssen et al., 2000; Kirk et al., 2020c; Riggs et al., 2008; Wilkinson
The musculoskeletal system comprises muscle, bones, and joint et al., 2018). The interaction of multiple factors such as reduced physical
connective tissue. Its shared function extends beyond structural support, activity, comorbidities like diabetes mellitus, and nutritional and hor­
protection of internal organs, and movement allowance. It also mediates monal alterations induce the musculoskeletal changes associated with
humoral processes and is a reservoir of organic and inorganic molecules aging and drive an individual’s musculoskeletal health status to surpass
to maintain the entire organism’s homeostasis (Boros and Freemont, a pathological threshold, thereby paving the way for musculoskeletal
2017). Given the accelerated population aging, the importance of a diseases such as osteosarcopenia (Leser et al., 2021; Wan et al., 2021).
healthy aging process becomes increasingly relevant. In this sense, the Osteosarcopenia, defined as the combination of sarcopenia and
success of achieving this goal is tightly connected to the intrinsic ca­ osteopenia/osteoporosis, is considered a geriatric syndrome due to its
pacity of the individual and its functionality, therefore, efforts to higher prevalence in the older population and its adverse health con­
maintain healthy aging must consider its relationship with the muscu­ sequences(Hassan and Duque, 2017), significantly increasing the risk of
loskeletal system and its age-related changes (Xia et al., 2019). falls, fractures, disability and mortality (Chen et al., 2024; Salech et al.,
The age-related changes in muscle and bone include decreased mass, 2021). For this reason, it becomes necessary to understand the patho­
quality, and function. A reduction in trabecular number and thickness physiological mechanisms involved in developing osteosarcopenia to
has been described in bone, along with cortical thinning and increased establish direct therapeutic efforts toward targets that simultaneously
porosity (Chen et al., 2013a). Similarly, there is a decrease in muscle affect both tissues (Kirk et al., 2019).
mass due to atrophy and a reduction of muscle fibers and satellite cells, The hallmarks of aging were proposed in 2013 by López- Otín as a
which are associated with the selective loss of type II motor neurons conceptual framework for a comprehensive and integrative under­
(Mahindran et al., 2021). Both changes occur after reaching a peak standing of aging’s complexity, facilitating aging research (López-Otín
density of bone and muscle in early adulthood, initially with a gradual et al., 2013). Currently, and after adding three new hallmarks in 2023
deterioration that becomes significant from the fifth decade of life, with (López-Otín et al., 2023), a total of twelve hallmarks of aging have been
a substantial and progressive rate of deterioration in bone mineral described, which meet the criteria for being considered as such,

* Correspondence to: 1001 Decarie Blvd, Room EM1.3226, Montreal, QC H4A 3J1, Canada.
E-mail address: [email protected] (G. Duque).

https://doi.org/10.1016/j.mad.2024.111997
Received 11 June 2024; Received in revised form 6 October 2024; Accepted 10 October 2024
Available online 11 October 2024
0047-6374/© 2024 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/).
F. Franulic et al. Mechanisms of Ageing and Development 222 (2024) 111997

including 1) the time-dependent manifestation of alterations accompa­ damage sensing, as well as in nuclear and mitochondrial DNA repair,
nying the aging process, 2) the possibility to accelerate aging by leading to genomic instability with a tendency to present mutations and
experimentally accentuating the hallmark, and 3) the opportunity to accumulation of ectopic DNA in the cytosol. If perpetually unresolved,
decelerate, halt, or reverse aging by therapeutic interventions on the this leads to the activation of pathways related to apoptosis or cellular
hallmark. For a better understanding of the complex aging process, it is senescence (López-Gil et al., 2023; López-Otín et al., 2023).
crucial to grasp the concept of interdependence among the effects of The impact of genomic instability on the mechanisms involved in the
each hallmark on one another. Thus, the twelve hallmarks have been development of osteoporosis and sarcopenia has been explored through
grouped according to common mechanisms that lead to aging: primary an accelerated aging model in animals, via the deletion of the Ercc1 or
hallmarks, which have an unfavorable effect and trigger the accumu­ XPF genes, due to the loss of DNA repair mechanisms (Yılmaz et al.,
lation of damage; antagonistic hallmarks, whose effect depends on the 2024). In mutant murine models Ercc1-/Δ, bone architecture and den­
intensity of their activity, potentially being beneficial or, conversely, sity changes occur, which resemble age-related osteoporosis, alongside
promoting the activity of primary hallmarks; and finally, integrative alterations in osteoblast function and increased osteoclastogenesis
hallmarks, which affect the homeostatic mechanisms of tissues and (Chen et al., 2013b). On the other hand, Ercc1-/Δ mice exhibit a
hinder the response to damage by the first two (López-Otín et al., 2023; phenotype associated with sarcopenia, displaying reduced grip strength
Tenchov et al., 2024). and muscle function compared to controls, as well as decreased muscle
Geroscience, which studies the interaction between the physiology of mass. Additionally, an upregulation of the Akt pathway is observed,
aging and the development of age-associated chronic diseases, provides suggesting a compensatory mechanism for muscle hypertrophy. How­
a theoretical and practical framework for the structured organization of ever, this ultimately results in net muscle loss due to the deregulation of
current knowledge and the planning of new development lines. Ger­ protein synthesis and autophagy pathways (Alyodawi et al., 2019).
oscience has aimed at understanding the aging processes at all its levels Similarly, the relationship between genomic instability at the mito­
(genetic, molecular, cellular) to generate interventions that halt or delay chondrial level and the development of osteosarcopenia has been
the onset and the progression of mechanisms leading to age-related investigated through the use of prematurely aged PolgA mice, charac­
diseases and disabilities (Anton et al., 2020). In the field of ger­ terized by a deficiency in DNA polymerase γ, the enzyme solely
oscience, the study of musculoskeletal aging through mouse models responsible for mitochondrial DNA replication and repair. PolgA mice
offers the advantage of similarities to human aging, as well as requiring exhibited an accelerated aging phenotype compared to their wild-type
less time to evaluate the onset of aging phenotypes and response to in­ (WT) littermates. At 40–46 weeks, PolgA mice displayed phenotypes
terventions. These models are an excellent source for studying molecular consistent with osteosarcopenia, demonstrating a progressive pattern of
processes and potential interventions in osteosarcopenia (Xie et al., musculoskeletal weakness with age, including reduced muscle strength
2021; Yılmaz et al., 2024). and performance. Additionally, bone microarchitecture was assessed
This review aims to describe the literature that reports the state of using micro-CT between 20 and 40 weeks of age, revealing a divergence
the art on hallmarks of aging in pre-clinical studies involved in the in bone morphometrics from 20 weeks onward, transitioning from
development of osteosarcopenia (Fig. 1), prioritizing findings from the similar values between genotypes to a decremental pattern in PolgA
last decade and those specifically addressing concurrent impacts on mice as they age (Scheuren et al., 2020). Therefore, the impairment of
muscle and bone. mitochondrial DNA repair mechanisms appears to be linked to muscu­
loskeletal structure and function.
2. Hallmarks of aging and osteosarcopenia
2.1.2. Telomere attrition
2.1. Primary hallmarks Telomeres, repetitive sequences of nucleotides, play a crucial role in
maintaining chromosome integrity and genomic stability (Tenchov
2.1.1. Genomic instability et al., 2024). They achieve this through structural protection mecha­
The genome is constantly exposed to sources of intra and extracel­ nisms that prevent chromosome end fusion (de Lange, 2002; Tenchov
lular damage that require repairing mechanisms of genetic material to et al., 2024) and guard against DNA loss at the ends during cell division,
prevent damage accumulation. With aging, there is a loss of efficiency in which is a determinant of cellular replicative potential (Hayflick limit)

Fig. 1. Interaction between risk factors for the development of osteosarcopenia and the amplified effects of the hallmarks of aging on muscle and bone, leading to
osteosarcopenia and its outcomes.

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F. Franulic et al. Mechanisms of Ageing and Development 222 (2024) 111997

(Shay and Wright, 2000). To maintain telomere length and normal diseases, proteostasis collapse can occur due to the disruption of any of
function, protein complexes such as Shelterin and the CST these stages, leading to the aggregation of polypeptides and the accu­
(CTC1-STN1-TEN1) complex exist. The Shelterin complex inhibits mulation of misfolded proteins (Kaushik and Cuervo, 2015; López-Otín
damage signals at telomere ends known as DNA damage response (DDR) et al., 2023).
and allows access to telomerase, a specialized DNA polymerase crucial The role of proteostasis loss in the development of osteosarcopenia is
for highly replicative tissues. The CST complex, on the other hand, evident in Zmpste knockout mice (Zmpste24-/-), where a metal­
prevents telomere over-elongation (Gao et al., 2022). loproteinase responsible for processing Lamin A, a component of the
Several studies have demonstrated that telomere dysfunction or nuclear lamina crucial for genomic stability, is deficient. These
downstream DDR signalling pathways can accelerate cellular senescence accelerated-aging mouse models exhibit alterations consistent with
and disease development (Gao et al., 2022; White et al., 2015). osteosarcopenia. In bone, multiple spontaneous fractures from early
Regarding to osteoporosis, a clear relationship has been observed be­ ages were reported, along with a decrease in trabecular and cortical
tween telomeric dysfunction and the loss of osteoblastic proliferative bone volumes in micro-CT scans. Histological sections revealed acellu­
and differentiation capacity (Saeed et al., 2011; Wang et al., 2012), larity at fracture sites, minimal inflammatory infiltrate, and no evidence
however, there is less clear and limited evidence regarding telomere of recovery (Bergo et al., 2002). Additionally, there was a lower number
length and its association with the development of sarcopenia (Ludlow of osteoblasts and osteocytes, along with increased adipogenesis in the
et al., 2014) and osteosarcopenia (Kirk et al., 2022) (Kirk et al., 2024). bone marrow (Rivas et al., 2009). Furthermore, Zmpste24-/- mice
To date, there are two population-based observational studies using showed slowed gait and muscle weakness compared to their littermates
data from the UK Biobank. The first study included 20,400 participants, (Bergo et al., 2002). These findings were consistent with a later study
an average age of 68 years. It found no association between leukocyte that demonstrated reduced muscle force generation and muscle
telomere length (LTL) and osteosarcopenia or its components of bone contraction performance, highlighting a pattern of selective weakness in
mineral density, muscle mass, or strength (Kirk et al., 2022). The second certain muscle groups (Greising et al., 2012).
study, conducted by the same author, included 16,356 adults with an
average age of 63 years. It investigated the association of LTL with 2.1.5. Disabled macroautophagy
muscle and bone quality related to aging, considering the interconnec­ Autophagy is a cellular process that involves the degradation and
tion of fat infiltration in determining the quality of these tissues (Kirk recycling of cellular components, providing cells with energy and
et al., 2024). The results showed a strong association between LTL and building blocks for renewal. It is crucial for maintaining cellular ho­
thigh fat-free muscle mass, with stronger associations in men than meostasis and function by removing damaged organelles, misfolded
women. However, LTL was not associated with bone mineral density, proteins, and pathogens. As organisms age, autophagy efficiency de­
trabecular bone score, or muscle fat infiltration. clines, contributing to the accumulation of cellular debris and
Considering these results, there does not seem to be a direct associ­ dysfunctional proteins (López-Otín et al., 2023; Xie et al., 2023a). This
ation between telomere attrition and the development of musculoskel­ decline is associated with several age-related diseases, including neu­
etal disease, which is likely related to differences in the replicative rodegeneration, cardiovascular disorders, and cancer. Enhanced auto­
capacity of the tissues. phagy has been linked to increased lifespan and improved health in
various models, suggesting its potential as a therapeutic target to miti­
2.1.3. Epigenetic alterations gate aging effects and prolong health span. (Xie et al., 2023a; Xie et al.,
Epigenetic changes refer to usually reversible mechanisms that can 2023b)
affect gene expression without direct alterations to DNA sequences. Autophagy plays a crucial role in maintaining bone and muscle
These changes involve the interplay between the genome and the health (Klionsky et al., 2021) In animal models, disturbances in auto­
environment and determine alterations in gene transcription and disease phagy mechanisms have been shown to contribute to osteoporosis and
development (Saul and Kosinsky, 2021). The involvement of many sarcopenia. In the context of osteoporosis studies in mice, impaired
enzymatic systems and protein complexes is necessary to initiate and autophagy in osteoblasts and osteocytes results in decreased bone den­
maintain these changes. These systems participate in modifications at sity and disrupted bone remodeling processes. These cells fail to effec­
the level of histones, DNA methylation, chromatin remodelling, and tively replace old bone with new, leading to brittle and fragile bones.
dysfunction of non-coding RNA (López-Otín et al., 2023). Optineurin (OPTN) is an autophagy receptor that participates in fat
Among the epigenetic modifications described in the mechanism of differentiation in bone marrow mesenchymal stem cells (MSCs).
degenerative musculoskeletal diseases is the involvement of the OPTN-deficient mice exhibit elevated bone loss, exacerbated bone-fat
Enhancer of zeste homolog 2 (EZH2). This protein complex modulates imbalance and impaired autophagy and senescence, similar to aged
chromatin structure and regulates gene expression in cellular prolifer­ mice (Liu et al., n.d.).
ation and differentiation processes. Its role in osteoporosis has been Similarly, compromised autophagy is linked to a reduction in muscle
elucidated in bone, primarily through its action on bone marrow mass and function in muscle tissue. Autophagy is a crucial regulator of
mesenchymal stem cells (BMSCs), leading to an imbalance between muscle physiology, and its dysfunction related to aging affects muscle at
osteogenic and adipogenic pathways and promoting osteoclast activa­ various levels. It plays a significant role in the functionality of satellite
tion. In muscle tissue, EZH2 can impact satellite cell regeneration, cells, regulating their capacity to exit the quiescent state (Wen and
promote senescence, and contribute to cellular damage accumulation, Klionsky, 2016) Additionally, autophagy directly influences muscle
thereby leading to sarcopenia (Ma et al., 2023). Recent research has function. The depletion of dynamin-related protein 1 (Drp1), a GTPase
begun to explore epigenetic changes in an integrated manner in both that facilitates mitochondrial fission, impairs autophagy, triggers
tissues. There is evidence of a difference in mRNA expression in older oxidative stress, and damages mitochondrial function, thereby exacer­
females with osteosarcopenia compared to those with osteoporotic hip bating muscle degeneration and atrophy in aged mice (Dulac et al.,
fractures without sarcopenia, identifying an RNA sequencing profile 2021). These findings underscore the potential of targeted autophagy
with significant differences in the expression of 15 genes involved in the modulation as a therapeutic strategy for treating osteoporosis and sar­
phagosome and endocytosis-related pathways (Kang et al., 2021). copenia, highlighting its importance in the aging process of bone and
muscle tissues (Cordero et al., 2022).
2.1.4. Loss of proteostasis
Cellular control mechanisms operate during protein production,
maintenance of spatial conformation, and protein degradation processes
to maintain proteome homeostasis (proteostasis). In aging and related

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F. Franulic et al. Mechanisms of Ageing and Development 222 (2024) 111997

2.2. Antagonistic hallmarks dysfunction in the NRF2-ARE pathway is associated with muscle atrophy
(Miller et al., 2012), decreased physical function (Huang et al., 2019),
2.2.1. Deregulated nutrient sensing and impaired regenerative capacity of satellite cells (Al-Sawaf et al.,
Deregulated nutrient sensing in aging refers to the impaired ability of 2014). Conversely, activation of this pathway allows for the mainte­
cells to manage nutrient uptake and utilization, contributing to age- nance of healthy muscle function and mass (Al-Sawaf et al., 2014;
related diseases and diminished cellular function and longevity. The Gumeni et al., 2021). On the other hand, in bone, the results of animal
AKT/mTOR/FOXO pathway is central to regulating cell growth, meta­ studies have been controversial. While most have demonstrated that
bolism, and survival. Activation of AKT by growth signals leads to mTOR Nrf2 knockout impairs bone metabolism (Zhang et al., 2023), the
stimulation, enhancing cell growth and inhibiting autophagy. response associated with Nrf2 agonism or inhibition differs depending
Conversely, AKT suppresses FOXO transcription factors, which are on the type of bone cell, the level of activation intensity, and sexual
crucial for promoting genes related to cell cycle arrest, apoptosis, and dimorphism (Han et al., 2022).
antioxidant defense (Kennedy and Lamming, 2016). Disruption in this
pathway is linked to various diseases, health, and aging, including 2.2.3. Cellular senescence
muscle and bone diseases. Sasako et al. (2022) showed that mice with Cellular senescence is a state in which cells cease to divide but
skeletal muscle-specific double knockout of Akt1/2 develop premature remain metabolically active, often in response to stress or damage. This
osteopenia and sarcopenia. These phenotype characteristics were process can be part of physiological processes such as bone growth
reversed by knocking out Foxo1/4 - an activator of the mTOR pathway - during early puberty(Liu and Wan, 2019), beneficial as a defense
suggesting that suppression of Akt activity could accelerate osteo­ mechanism against cancer(Serrano et al., 1997), or conversely, can
sarcopenia phenotype. contribute to aging when senescent cells accumulate, leading to
Insulin-like 1 (IGF-1) and interleukin-6 (IL-6) signalling in the heightened inflammation, tissue dysfunction, and a decline in regener­
regulation of skeletal muscle adaptation and bone metabolism. These ative capacity (Chaib et al., 2022). This accumulation of senescent cells
factors can affect myofibers, muscle stem cells (MuSCs), and cells in is associated with many age-related diseases, including those related to
other organs such as the liver and potentially bone. IGF-1 stimulates the frailty and musculoskeletal diseases (Marcozzi et al., 2023) such as
rate of protein translation in myofibers via the phosphatidylinositol 3 osteoporosis and sarcopenia (Gerosa et al., 2023)
kinase (PI3-K)/Akt/mammalian target of rapamycin (mTOR) pathway, In osteoporosis, senescent cells disrupt normal bone remodeling by
and IL-6 stimulates the proliferation and differentiation of satellite cells secreting pro-inflammatory factors that degrade bone matrix and inhibit
via the Janus kinase/Signal Transducer and Activator of Transcription the formation of osteoblasts (Farr and Khosla, 2019; Pignolo et al.,
(JAK/STAT) pathway, both pathways relevant for nutrient sensing 2021). Studies in aged mice have observed the accumulation of senes­
process. Furthermore, mechanically-loaded osteocytes and osteoblasts cent cells in both bone and bone marrow, affecting osteoprogenitor cells,
produce IGF-1 and IL-6, connecting movement, bone-muscle health, and osteoblasts and osteocytes. These senescent cells acquire a secretory
hallmarks of aging (Bakker and Jaspers, 2015). phenotype (SASP), inducing a response that favors bone resorption
through pro-osteoclastogenic cytokines, such as receptor activator of
2.2.2. Mitochondrial dysfunction nuclear factor kappa beta ligand (RANKL). (Farr et al., 2016; Kim et al.,
Mitochondrial function plays a crucial role in cellular energy de­ 2017). The accumulation of senescent cells in bone tissue leads to
mand adaptation. Additionally, its involvement through intermediary decreased bone mass and increased fragility, and targeted removal of
metabolites is necessary for intracellular signaling processes and im­ these cells has been found to restore bone growth and improve structural
mune response, pathways leading to either an inflammatory activation integrity, suggesting a direct link between senescence and bone density
state or cell death (Phua et al., 2024). deterioration(Farr et al., 2017).
The decline in mitochondrial function has been of particular interest Similarly, in muscle satellite cells, a shift from their characteristic
due to its association with age-related diseases as well as the aging quiescent state towards acquiring a senescent state has been reported in
process itself (Min et al., 2024). Consequently, a decrease in energy aged murine models, evidenced by the expression of the p16Ink4a
metabolism efficiency has been described, leading to an increase in mRNA marker, leading to the loss of their regenerative functions in the
reactive oxygen species (ROS). When present in excess, ROS cause muscle (Sousa-Victor et al., 2014). Furthermore, the involvement of
oxidative damage to DNA, as well as mitochondrial protein structures senescence in the mechanisms underlying sarcopenia development has
and membranes, creating a vicious cycle of mitochondrial dysfunction. been described through senescence-accelerated mouse prone models
This dysfunction further diminishes mitochondrial dynamics and hin­ (SAMP), specifically in SAMP8 mice, which show reduced muscle mass
ders mitophagy (Guo et al., 2023) and strength as evidenced by decreased grip strength, contractile ca­
Disruption of the mitochondrial permeability transition pore pacity, and type II fibers (Liu et al., 2020). Experimental models where
(mPTP), a central mechanism in response to pathological mitochondrial senescent cells were cleared from aged mice resulted in enhanced
stress, has been linked in animal and human models to loss of muscle muscle regeneration and increased strength, underscoring the detri­
mass and function. This disruption leads to an overproduction of reac­ mental role of senescence in muscle aging (Cosgrove et al., 2014; X.
tive oxygen species (ROS), which in turn favor catabolic pathways, pro- Zhang et al., 2022).
inflammatory pathways, and apoptosis (Leduc-Gaudet et al., 2021). In
the case of bone tissue, increased MPTP activity and its positive regu­ 2.3. Integrative hallmarks
lator (cyclophilin D) have been described in aged mouse models
compared to young mice (Sautchuk et al., 2020). Subsequently, a causal 2.3.1. Stem cell exhaustion
relationship was demonstrated between the overactivation of these Stem cells are unique cells that can self-renew and differentiate into
mechanisms and metabolic changes in osteoblasts leading to bone other cell types according to their potency, thereby maintaining normal
fragility (Sautchuk et al., 2020). tissue function and regenerating injured tissue (López-Otín et al., 2023).
One of the protective mechanisms against excess ROS is the Nuclear The interaction of the hallmarks of aging described above would lead
factor-erythroid 2 related factor 2 (NRF2), which maintains redox ho­ these cells towards senescence and the depletion of their capabilities,
meostasis by activating pathways related to antioxidant response within resulting in a reduction in their number, regenerative capacity, and
the cell. It also participates in modulating mitochondrial permeability clonality (Kirk et al., 2019; Ren et al., 2017).
and cellular apoptosis, thereby influencing processes of differentiation, Mesenchymal stem cells (MSCs) can differentiate into various cell
maintenance, and cell proliferation in musculoskeletal pathology types, including those belonging to osteogenic, myogenic, and adipo­
(Zhang et al., 2023). In muscle, murine models have shown that genic lineages (Benayahu, 2022). In animal models, changes associated

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F. Franulic et al. Mechanisms of Ageing and Development 222 (2024) 111997

with aging in regenerative capacity and cellular plasticity have been (Artaza et al., 2005; Elkasrawy and Hamrick, 2010), evidenced in
evaluated separately in muscle and bone tissue, revealing a lower con­ studies with myostatin knockout mice, which exhibit increased muscle
tent and proliferation rate as the regenerative capacity of myofibers in mass, (McPherron et al., 1997) higher bone mineral density and
satellite cells in muscle (Lavasani et al., 2012; Snijders and Parise, 2017; enhanced osteogenic differentiation (Hamrick et al., 2007). Conversely,
Yamakawa et al., 2020), as well as an age-associated decrease in the in murine models, growth factors like IGF-1 and FGF-2 positively affect
number and proliferative capacity of bone marrow stem cells derived both tissues, stimulating their formation and regeneration (Sheng et al.,
from old rats (Asumda and Chase, 2011). Additionally, diverse pop­ 2023; Yakar and Isaksson, 2016). Knockout models of these factors
ulations of skeletal/stem progenitor cells residing in the growth plate, exhibit the opposite effect, along with increased lipid accumulation in
periosteum, and calvarial sutures showed diminished proliferative ca­ these tissues (Homer-Bouthiette et al., 2021; Montero et al., 2000).
pacity, as identified through scRNA-seq (Mancinelli and Intini, 2023). Another way of cell-cell communication is through extracellular
The regenerative capacity of MSCs has garnered particular interest vesicles secreted by a cell and acting upon neighboring or distant target
due to their therapeutic potential in musculoskeletal pathologies. Evi­ cells by delivering proteins, microRNAs (miRNA), and mRNAs. They
dence from murine models has demonstrated that MSC treatment, either participate in tissue homeostasis regulation as well as in propagating
through transplantation or local injection, has beneficial effects on damage associated with the hallmarks of aging, such as oxidative stress,
muscle and bone tissue (Mahindran et al., 2021). In the former case, in to other tissues, potentially leading to pathological states like osteo­
hindlimb suspension models, it enables the maintenance of an active sarcopenia (Qin and Dallas, 2019). In aged murine models, changes in
pool of satellite cells, reduces cellular apoptosis, and decreases inflam­ muscle-bone crosstalk have been described concerning the levels of
mation (Li et al., 2016; Wang et al., 2018). In the latter case, infusion of serum EV-miRNA released by these tissues, which determine alterations
MSCs from young mice to old mice improved trabecular architecture, in metabolism or promote cellular senescence, with unclear functions on
bone mineral density, and lifespan (Shen et al., 2011). Interestingly, bone/muscle in some cases (He et al., 2020). A recent systematic review
according to the results of a study in rabbits, the effect of aging on the identified a moderate degree of overlap in dysregulated miRNA between
regenerative capacity of MSCs in terms of proliferation, senescence, and osteoporosis and sarcopenia but with distinct activity patterns. Among
differentiation potential behaves differently depending on the cell them are miR-206, miR-208, miR-222, miR-328, miR-93, miR-155,
population. Specifically, the proliferative capacity of old bone marrow miR-23a-3p, miR-29a, and miR-133a and b, with implications yet to be
stem cells (BMSCs) is significantly reduced compared to muscle derived determined concerning these changes (Salamanna et al., 2023).
stem cells (MDSCs) and adipose-derived stem cells (ASCs) populations.
This finding underscores the importance of considering the potential 2.3.3. Chronic inflammation (inflammaging)
source of MSCs when choosing candidates for regenerative treatments In aging, a state of chronic, low-grade, and unresolved inflammation
(Beane et al., 2014). has been described. This condition arises from the accumulation of tis­
sue damage, the pro-inflammatory secretome of senescent cells, and
2.3.2. Altered intercellular communication dysfunction in the adaptive immune system, leading to the loss of
To maintain inter-organ coordination, communication between cells tolerance and defective immunosurveillance (Fulop et al., 2021; Li and
from different tissues is necessary, either through the release of soluble Ma, 2024; López-Otín et al., 2023). Consequently, this leads to a
factors, direct cell-cell, or cell-extracellular matrix interactions. This pro-inflammatory systemic environment characterized by increased
communication aims to induce changes in tissue function in response to activity of NF-Kb and circulating levels of pro-inflammatory markers
physiological or pathological conditions (Fafián-Labora and O’Loghlen, such as IL-6, TNF-alpha, and CRP (Li et al., 2023; López-Otín et al.,
2020). Associated with aging, alterations in intercellular communica­ 2023), which interact bidirectionally with the other hallmarks of aging.
tion have been described in bone and muscle tissues, characterized by Coupled with the interaction with adipose tissue infiltration, this pro­
changes in cellular secretory profiles, the presence of motes the development of diseases that affect survival and functionality,
senescence-associated secretory phenotype (SASP) (He et al., 2020) and such as cardiovascular diseases, Alzheimer’s disease, and osteosarco­
alterations in the microenvironment of cellular niches that hinder penia (Baechle et al., 2023; Huang et al., 2022).
intercellular interactions (Thorley et al., 2015). Adding to this scenario, Studies in both humans and animals have described the unfavorable
the negative influence of fat infiltration in tissues and reduced physical effect of this chronic inflammation on bone and muscle tissue (Michaud
activity establishes a pathological pathway toward osteosarcopenia et al., 2013). In bone tissue, chronic inflammation promotes bone
(Kaji, 2023). resorption by activating osteoclastogenesis through TNF-alpha, which
In the last decade, communication between bone and muscle has increases the expression of RANKL and expands the pool of osteoclast
garnered significant interest in the field of geroscience due to the op­ precursors through macrophage colony-stimulating factor (M-CSF)
portunity to modulate age-related musculoskeletal conditions, including (Marahleh et al., 2019). Additionally, it leads to dysfunction and
osteosarcopenia (Yılmaz et al., 2024). The relationship between these reduced survival in osteoblastic progenitors (Josephson et al., 2019; Xu
tissues is considered a muscle-bone unit, owing to the close link they et al., 2023). In the case of muscle tissue, sustained systemic inflam­
share (Tagliaferri et al., 2015). This interaction is characterized as mation, characterized by increased levels of pro-inflammatory cytokines
reciprocal, dynamic, and multi-level (cellular, tissue, organism), such as IL-6 and TNF-alpha, would increase muscle catabolism and
occurring through signaling mechanisms related to mechanical loading decrease muscle cell differentiation, promoting or accelerating a sar­
(Herrmann et al., 2020), as well as biochemical factors including hor­ copenic phenotype (Liang et al., 2022).
monal factors from the somatotropic axis (Young et al., 2022) and In the development of osteosarcopenia, the interplay of adiposity
substances secreted by the muscle (myokines), bone (osteokines), and accumulation and adipokines, including IL-6 and TNF-alpha, cannot be
infiltrating adipose tissue (adipokines), regulated mainly through overlooked. These factors create a state of low-grade inflammation both
physical activity (Kirk et al., 2020a). These substances consist of cyto­ systemically and locally, promoting bone marrow adiposity and accel­
kines and growth factors that exert their effects in an autocrine, para­ erating bone resorption, as well as promoting muscle catabolism (Kirk
crine, or endocrine manner, determining changes in cellular metabolism et al., 2020a).
(anabolism/catabolism) to achieve homeostasis in the musculoskeletal The aged-related immune changes and their synchronous effect on
tissue (Kirk et al., 2019). the musculoskeletal system have been evidenced in a recent single-cell
Hundreds of myokines and osteokines have been described with their RNA sequencing study. In this research, the cellular composition in
metabolic effects on tissues elucidated through animal models, though muscle and bone of older and younger subjects was evaluated in parallel.
not entirely clear in humans (Kirk et al., 2020b). Certain myokines have A subset of lipid-associated macrophages (TREM2+ Macs) emerged
a negative regulatory effect on both muscle and bone, such as myostatin exclusively in aged muscle and bones, sharing characteristics similar to

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F. Franulic et al. Mechanisms of Ageing and Development 222 (2024) 111997

those macrophages present in fatty liver or obese adipose tissue. On the pathogenic organisms with age ( Lee et al., 2021a).
other hand, the T cells residing in aged muscle and bones exhibit pro-
inflammatory characteristics. However, in the genetic enrichment 3. Clinical applications and future perspectives
analysis, CD4+ T cells show differences, with a predominance of Th1-
like cells in muscle and a Th17 profile in bone, highlighting the differ­ Considering the impact of osteosarcopenia on the health and quality
ences between both tissues (Yin et al., 2024). of life of older individuals, it is essential to find therapeutic alternatives
that have a dual effect on both tissues. In this respect, a greater under­
2.3.4. Dysbiosis standing of the hallmarks of aging through recent preclinical studies has
Dysbiosis is a novel hallmark of aging that involves disruptions in the positioned them as potential targets for clinical interventions, such as
reciprocal communication between the microbiota and the host, essen­ the use of senolytics or senomodulators designed to eliminate or modify
tial for multiple physiological processes (López-Otín et al., 2023). the functioning of senescent cells (Cordero et al., 2022) or the use of
Studies in humans and animals have demonstrated reduced diversity pharmacological mTOR modulators (Lin et al., 2022). However, to date,
and lower microbiome stability with aging (Buford, 2017), with mi­ no specific pharmacological treatment for osteosarcopenia has been
crobial composition patterns associated with various trajectories in approved for humans. Recently, a systematic review was published
health and longevity (Badal et al., 2020; López-Otín et al., 2023). analyzing rapamycin analogs, or "Rapalogues," and their effects on
An intact gut microbiome is essential for bone and muscle health. Its human age-related musculoskeletal disorders (Lin et al., 2022). The
interaction with the musculoskeletal system involves mechanisms study revealed opposing effects on both tissues, demonstrating an
related to immunomodulation by maintaining intestinal barrier integrity anabolic effect on bone with a decrease in biomarkers of osteoclastic
and balance in pro and anti-inflammatory cytokines. Additionally, it activity alongside a reduction in muscle protein synthesis. However,
influences the production of microbial metabolites such as the short- interpreting these results must be cautiously approached due to the di­
chain fatty acid (SCFA) that promotes bone and muscle formation and versity in study designs and the populations’ ages, suggesting a theo­
regulates inflammation pathways (Li et al., 2021; T. Zhang et al., 2022). retically positive effect on both tissues if the studied population were
Specifically, concerning bone metabolism, its involvement has been older (Lin et al., 2022). On the other hand, based on the muscle-bone
described in the absorption of vitamin D and calcium and the regulation crosstalk mechanism, Denosumab has been proposed as a treatment
of IGF-1 and sex hormone levels (Charles et al., 2015), as well as in the for osteosarcopenia. An observational study showed improved muscle
regulation of the function of lymphoid cells in the gut, mainly CD4+ performance in postmenopausal women with osteoporosis treated with
Th17 helper cells that promote osteoclastogenic action in mice and Denosumab (Bonnet et al., 2019). Despite its therapeutic potential, no
humans in pro-inflammatory environments (Ibáñez et al., 2019). On the subsequent clinical studies have supported its direct effect on muscle.
other hand, it regulates protein anabolism and mitochondrial function in The non-pharmacological approach through exercise is a promising
muscle (Prokopidis et al., 2021). strategy, considering its modulating effect on mechanisms such as
The diversity in the microbiome is not only associated with age but cellular senescence, oxidative stress, dysfunctional macroautophagy,
also with genetic factors, diet, and host comorbidities, which should be and inflammation (Leser et al., 2021). Resistance exercise also affects
considered when investigating its effect on musculoskeletal aging the crosstalk between bone, muscle, and fat, promoting muscle mass
(Steves et al., 2016). In patients with sarcopenia, a higher abundance of formation and bone density, increasing insulin sensitivity, and reducing
Porphyromonadaceae has been reported, which is associated with adipose tissue (Kirk et al., 2020a). It has been demonstrated through a
metabolic syndrome, along with a decrease in Lachnospiraceae, which clinical trial that the combination of high-intensity resistance training
plays a role in SCFA metabolism (Nikkhah et al., 2023). Regarding and proper supplementation with protein, calcium, and vitamin D are
osteoporosis, there has been a reported increase in opportunistic path­ effective interventions for treating osteosarcopenia in older men
ogens such as Clostridium sensu stricto, Bacteroides, and Intestinibacter, (Kemmler et al., 2020).
along with a decrease in SCFA-producing microorganisms such as Col­ Other promising interventions still in development exist, such as
linsella, Megasphaera, Agathobaculum, Mediterraneibacter, Clos­ those targeting the kynurenine pathway. This is driven by its accumu­
tridium XIV, and Dorea (Akinsuyi and Roesch, 2023). lation linked to aging, stemming from integrative hallmarks like chronic
The relationship between dysbiosis and the development of osteo­ inflammation and dysbiosis, and its adverse impact on bone tissue and
porosis and sarcopenia has been evaluated in individual mice models. muscle (Ballesteros et al., 2023). Considering the effects of the hallmarks
Germ-free (GF) mice show lower muscle function and mass, which is of aging on bone and muscle metabolism, it is expected that both
improved by transplantation of microbiota from their peers, resulting in pharmacological and non-pharmacological anti-aging interventions will
increased muscle mass, greater muscle oxidative capacity, and expres­ someday treat osteosarcopenia.
sion of neuromuscular junction genes. Additionally, treatment with a
cocktail of SCFA partially reversed the atrophy and muscle strength in 4. Conclusion
these GF mice (Lee et al., 2023). In contrast, GF murine models exhibit
higher trabecular bone mass at the expense of reduced osteoclastic ac­ This article comprehensively reviewed the currently available liter­
tivity and lower frequencies of CD4+ T cells and osteoclast precursor ature on the role of the hallmarks of aging in the development of
cells in the bone marrow. Normalization of all these parameters occurs osteosarcopenia, thereby offering a panoramic view of the state of the
upon colonization of these mice with normal microbiota (Sjögren et al., art and knowledge gaps in this field.
2012). Subsequently, it was evidenced that the long-term action of the Osteosarcopenia is a significant driver of functional loss and a risk
microbiota and exposure to SCFA induce skeletal growth and remodel­ factor for disability and mortality in older adults, urgently requiring the
ing through IGF-1 (Cronin et al., 2022; Yan et al., 2016). development of effective interventions to address it (Duque, 2021). In
The beneficial effect of probiotics on muscle and bone function and this regard, Geroscience, which studies the interaction between the
mass has been extensively studied separately (Bindels et al., 2012; physiology of aging and the development of age-associated chronic
Chiang and Pan, 2011; Guo et al., 2022; Lee et al., 2021a; Lee et al., diseases, provides a theoretical and practical framework that allows for
2021b; Zhang et al., 2022), with few studies evaluating the effect on the structured organization of current knowledge and the planning of
both tissues. In a recent study assessing the administration of Lactoba­ new development lines (Kennedy et al., 2014). It is noteworthy that
cillus plantarum TWK10 in young and aged mice, a favorable effect was there is evidence linking each of the hallmarks of aging to biological
found on muscle function and glycogen levels, as well as a decrease in processes in bone and muscle, potentially associated with the develop­
age-related bone loss and bone quality. This was associated with a ment of osteosarcopenia. However, not all hallmarks carry the same
change in the microbiota composition, reducing the accumulation of weight of evidence in the development of osteosarcopenia. This

6
F. Franulic et al. Mechanisms of Ageing and Development 222 (2024) 111997

variation may stem from the lesser significance of certain biological aging and geroscience framework (Fig. 2), providing valuable infor­
mechanisms and/or a lack of knowledge development in that specific mation about potential new development lines and knowledge in the
field, presenting intriguing avenues for future exploration. Thus, it is search for efficient therapeutic options to address this condition.
essential to overcome one of the major challenges in this area, which is
the lack of animal models that simultaneously study both organs. In this Ethical Approval
regard, the contribution of the researchers and their work described in
this review is highly valuable. This review article does not present any unpublished original
Among the strengths of this study is the broad and unbiased search research, and ethical approval is therefore not applicable.
for literature on the role of hallmarks that have been studied in animal
models of osteosarcopenia. However, a key weakness is the lack of Author contributions
widely accepted animal models for the joint analysis of the pathophys­
iology of bone and muscle, with many of them investigating separately All authors contributed to the conceptualization, writing, review and
the effects of the same molecule on bone and muscle, not allowing a editing of this article.
complete understanding of the phenomenon of osteosarcopenia.
In summary, this review has compiled the current knowledge gath­
ered from animal models of osteosarcopenia using the hallmarks of

Fig. 2. Summary of evidence from preclinical research on the role of the hallmarks of aging in osteosarcopenia development.

7
F. Franulic et al. Mechanisms of Ageing and Development 222 (2024) 111997

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