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. Author manuscript; available in PMC: 2023 Mar 15.
Published in final edited form as: Curr Osteoporos Rep. 2022 Aug 31;20(5):326–333. doi: 10.1007/s11914-022-00745-8

Does Aging activate T-cells to reduce bone mass and quality?

Rajeev Aurora 1,*, Deborah Veis 2
PMCID: PMC10016147  NIHMSID: NIHMS1879820  PMID: 36044177

Abstract

Purpose of Review

Aging leads to decline in bone mass and quality starting at age 30 in humans. All mammals undergo a basal age-dependent decline in bone mass. Osteoporosis is characterized by low bone mass and further by changes in bone microarchitecture that increases the risk of fractures. About a third of men over the age of 50 years are osteoporotic because they have higher than basal bone loss. In women, there is an additional acute decrement in bone mass, atop the basal rate, associated with loss of ovarian function (menopause) causing osteoporosis in about half of the women. Both genetics and environmental factors such as smoking, chronic infections, diet, microbiome, and metabolic disease can modulate basal age-dependent bone loss and eventual osteoporosis. Here, we review recent studies on the etiology of age-dependent decline in bone mass and propose a mechanism that integrates both genetic and environmental factors.

Recent Findings:

Recent findings support that aging and menopause dysregulate the immune system leading to sterile low-grade inflammation. Both animal models and human studies demonstrate that certain kinds of inflammation, in both men and women, mediate bone loss. Senolytics, meant to block a wide array of age-induced effects by preventing cellular senescence, have been shown to improve bone mass in aged mice. Based on a synthesis of the recent data, we propose that aging activates long-lived tissue resident memory T-cells to become senescent and proinflammatory, leading to bone loss. Targeting this population may represent a promising osteoporosis therapy.

Summary:

Emerging data indicates that there are several mechanisms that lead to sterile low grade chronic inflammation, inflammaging, that cause age- and estrogen-loss dependent osteoporosis in men and women.

Introduction

Osteoporosis, or increased porosity of the bone, is a common skeletal disorder that leads to increased risk of fracture with minimal trauma [1, 2]. Age promotes osteoporosis, increasing the risk of bone fracture from a fall. Although fractures rarely directly result in death, there is increased mortality post-fracture in both men and women with low bone mineral density. Regardless of genetics and nutrient intake, men and women experience a decline in bone mass starting around age 30 (Fig. 1A) [3, 4]. In addition, women experience an acute phase of bone loss near menopause. In mice, peak bone mass is attained between 4 and 6 months, depending on strain, and declines thereafter[5]. Indeed, age leads to a decline of many physiological functions in all living organisms. There are several pathologies, such as atherosclerosis and cancers, which are classically associated with aging in mammals [6–8]. Based on many studies of aging in mammals and model organisms, López-Otín et al. identified nine cellular processes, the hallmarks of aging, that are dysregulated with time (aging) [9]. Of these nine processes, three viz. stem cell exhaustion, mitochondrial dysfunction, and dysregulated nutrient sensing, also undoubtedly promote waning of bone mass with age [10, 11]. However, the decline in bone mass begins at start of the 4th decade, while hallmarks of aging come into play later, at or after the 5th decade [9]. This timing suggests a different mechanism for loss to begin soon after attainment of peak bone mass. In this review, we attempt to identify physiological events that occur with aging and to reconcile their timing with age-dependent decline in bone mass. In addition to elaborating the mechanisms, the timing may also provide insights into which therapeutics may provide benefit to slow down age-dependent decline.

Fig 1. Relationship between age-related T-cell mediated inflammation and bone loss.

Fig 1.

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A. Bone mass as a function of age: Peak bone mass in men and women is reached in the mid-20s, and begins to decline ~age 30, coinciding with end of thymic involution. Modified from[115]. B. Three proposed mechanisms for increased T-cell inflammation with age. 1) Thymic involution decreases the output of ΤΝ (naïve T cells) and increases TM (memory T-cells) and TEFF (activated proinflammatory T-cells) in both sexes. TM live in a quiescent state for decades in the bone marrow, poised to reactivate. 2) In middle-aged men and women, anti-inflammatory TREG (FoxP3+ CD25+ CD4+) become senescent, increasing the levels of TEFF. 3) E2 loss at menopause in women increases TEM (effector memory T-cells) that produce proinflammatory cytokines. C. Mechanism by which E2 regulates TM and how E2 loss leads to TNFα and IL-17A and bone loss. E2 induces Fas ligand (FasL) in BM dendritic cells (DC) leading to apoptosis of the DC. TM in the BM require DC-derived IL-7 and IL-15 for their maintenance, so TM remain low in the presence of E2. After E2 loss, FasL is absent, leading to longer lived DC and higher levels of IL-7 and IL-15. Together, IL-7 and IL-15 lead to antigen-independent proliferation of TM which express TNFα and IL-17A and are now referred to as TEM. TEM cause uncoupled bone resorption[83].

Bone is remodeled throughout life to repair damage and maintain bone mass. The bone remodeling unit (BRU) is composed of osteoclasts (OC) that resorb bone and osteoblasts (OB) that form new bone. Healthy remodeling, initiated by hormonal, loading, environmental and nutritional factors, is coupled: resorption precedes formation and the amount of bone formed is balanced with the amount resorbed [12]. In osteoporosis, uncoupled resorption, i.e., bone removal that is not balanced by subsequent accrual, leads to weakened, osteoporotic bone that fractures with minimal trauma[13–15]. Aging and menopause are common etiologies of osteoporosis in all mammals. We contend that it seems logical to connect the observation that aging promotes decline in bone mass and concurrently low-grade inflammation to each other. Both men and women with chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and some viral infections (e.g., HIV and hepatitis), where TNFα, IL-17A or both are elevated, develop osteoporosis, supporting the notion that bone is sensitive to T-cell mediated inflammation [16–21]. Indeed, osteoimmunology arose from the recognition that T-cell-derived cytokines regulate the BRU [22, 23]. For example, TNFα and IL-17A increase OC differentiation [24, 25] by sensitizing OC progenitors to RANKL [26, 27]. Superimposed on the changes in T-cells driven by antigen are additional ones (detailed below) that occur with age and menopause. We propose that age- and hormone-related changes in T-cells subsets in the bone marrow promote inflammation, thereby driving bone loss (Fig 1B).

Aging impacts tissue resident memory T-cells

Infection leads to rapid conversion of naïve T-cells (TN) that recognize pathogen-specific antigens (Ag) to proinflammatory effector T-cells (TEFF) in the lymphoid organ [28]. TEFF clonally expand and recruit other immune cells to clear the infection, and TEFF levels wane as Ag is cleared[29]. A defining feature of the adaptive immune response is the formation of memory that is the basis for durable immunity[30–32]. Long after the acute Ag-specific response has faded, a subset of T-cells, memory T-cells (TM) carry the memory of an Ag exposure at the site of infection or immunization [33–35]. TM have an enhanced functional capacity to mount a response upon re-exposure [36]. Re-introduction of the Ag can convert TM to effector memory cells (TEM), which secrete similar inflammatory cytokines to TEFF. The type of response (e.g., polarization to TH1 or TH17) that was successful in clearing the pathogen is encoded by the TM and is the basis for the rapid and enhanced response upon re-encountering Ag [37, 38]. The encoding is mediated by epigenetic marks on the DNA and histones [39–41]. While TM remain at the site of Ag exposure and persist for years, a portion of the TM establish long-term residence (detectable after decades) in the bone marrow [42]. Other antigen exposures, from the environment (e.g., allergens and toxins) and the microbiome, also contribute to the TM pool within an individual. The long lifespan of TM makes them vulnerable to age-dependent changes. For instance, exposure to inflammatory signals, senescence and time may degrade epigenetic marks, promoting dysfunction or inappropriate activation (see below).

Genetic Studies of bone mass and aging immune system

A recent genome wide association study (GWAS) using 1.2 million individuals (both males and females) identified over 500 loci that affect bone mineral density (BMD)[43]. While GWAS have limitations, the finding that so many loci regulate BMD is striking. Saliently, the 500 loci account for ~ 20% of variance in BMD, consistent with prior studies [44–47]. These findings strongly support the notion that environment has a significant contribution to BMD and osteoporosis. GWAS of immune system using twins are also informative in this context [48, 49]. These studies indicate that the total number of T-cells produced (hematopoiesis and thymic output) is genetically regulated, but the TEFF and TM subsets produced from the naïve T-cells are dependent on environmental exposures. Taken together, the GWAS indicate that both bone mass and immune response are highly influenced by the environment. As a non-heritable factor, the effect of TM would not appear as a genetic locus in GWAS.

Thymic involution increases TM

In humans, thymic involution begins at about the 3rd year (postnatally) and this organ continues to decline, nearing complete atrophy by age 30 [50, 51]. Thymic involution leads to decreased naïve T-cells (TN) output. But as total T-cells stay constant, this leads to accumulation of TM and TEFF (Fig 1B, #1)[52, 53]. The inflammatory cytokines produced by TEFF, such as TNFα and IL-17A, uncouple bone remodeling, tipping the balance towards bone loss[23, 25, 54, 55] as observed in individuals with chronic infections. The age of thymic atrophy corresponds to the initial decline in bone mass after its peak (Fig 1A). Definitive experiments establishing cause-and-effect relationship between thymic atrophy and decline in bone mass are still lacking[56–58]. The figure is intended to show that the timing of near completion of involution and beginning of the decline in bone mass is coincident.

Senescence of TREG

Canonically, regulatory T-cells (TREG) are FoxP3 and CD25 expressing CD4 T-cells that are dominant negative regulators of the immune system[59, 60]. TREG are produced within and outside of the thymus [61, 62]. Depletion of TREG or genetic ablation of FoxP3 in CD4 T-cells leads to multi-organ inflammatory disease by allowing autoreactive T-cells to become activated [63–66]. TREG are long lived (half-life ~ years)[67]. With age, likely beginning after age 40, TREG become senescent and less functional, leading to increased activity of TEFF (Fig 1B, #2)[51, 68, 69]. Senescent TREG also secrete proinflammatory cytokines that contribute to an increased inflammatory burden, and thus likely to bone loss as well [70].

Many studies have highlighted the increase in senescent bone cells observed in aged mice [71–77]. These studies have not only shown an increase in p16Ink4a and p21Cdkn1a, markers associated with cellular senescence, in osteoblasts, osteocytes and OC, but also demonstrated that systemic administration of senolytics (drugs that target and reduce senescent cells[78]) reduce age related bone mass in animals [73]. However, the cellular target(s) of the senolytics have not been fully investigated [79]. It is possible that the targeting of senescent TREG by senolytics, and subsequent reduction of inflammation, plays a significant role in the preservation of bone.

Many of the studies, including treatment with senolytics, use 24-month-old mice [80, 81]. While these studies are important for understanding the effects of senescence in old bone, the use of mice of an advanced age does not explain what initiates bone loss observed after achieving peak bone mass (Fig. 1A). More studies coinciding with the onset of bone loss are needed.

Expansion of proinflammatory TRM with estrogen (E2) loss

Albright showed in 1946 that E2 decline around menopause initiates osteoporosis [82], but the precise mechanism linking E2 to the BRU has remained elusive. The loss of estrogen (E2) at menopause causes Ag-independent conversion of a subset of TM to TEM (Fig 1B, #3). Since thymic involution leads to accumulation of TM, there is a larger pool available to be converted into the highly inflammatory TEM population. The combination of TREG senescence and expansion of TEM at menopause may cause the higher rate of bone loss in middle-aged women compared to men (Fig 1A).

We have recently defined a novel pathway, dependent on IL-7 and IL-15 but antigen-independent, by which E2 loss leads to activation of memory T-cells (Fig. 1C). E2 regulates the lifespan of levels of IL-7 and IL-15 secreting dendritic cells (DC) by inducing Fas ligand in DC. In the absence of E2 (at menopause) these DC, no longer express Fas ligand, become long-lived leading to an abundance of IL-7 and IL-15. These two cytokines together (but not alone) lead to the proliferation of TM, and to expression of TNFα and IL-17A in a subset of the TM. Characterization of the TM activated by E2 loss shows that they are antigen experienced (CD44 positive) but lack expression of the cell surface protein (CD62L) needed to enter secondary lymphoid tissue; thus, they are defined as tissue resident memory T-cells (TRM)[83]. Once induced, TRM persistently express low-levels of TNFα and IL-17A[83]. To validate our model, we generated mice with a T-cell-specific (Lck-Cre) deletion of IL-15 receptor α chain (IL15RAΔT-cells). No induction of TNFα or IL-17A was observed in IL15RAΔT-cells mice post-OVX, demonstrating that both IL-7 and IL-15 are required for TM to become TEM. In the absence of TEM, no increase in resorption or loss of trabecular bone was observed in OVX IL15RAΔT-cells mice relative to sham-operated mice. Thus, E2 does not directly regulate the BRU to promote uncoupled resorption; rather, T-cell derived TNFα, and IL-17 are required [83]. These findings provide new mechanistic insights into a puzzle that has remained unsolved for eight decades: how does E2 loss lead to osteoporosis?

TRM are long lived and reside (quiescently) in host tissues to protect that tissue from re-infections but also home to the bone marrow to take up long-term residence[42]. As both the microbiota and TRM inhabit mucosal barrier sites, there is significant crosstalk between both cells[84]. Our finding that ovariectomy, specifically E2 loss, activates TRM also provides insights for how the gut microbiota modulates bone mass[85–87]. T cells specific to bacterial members of the microbiota differentiate into TH1, TH17, T Follicular Helper (TFH), and regulatory CD4 T cell (TREG) states[88]. However, which of these T-cell differentiation states is induced in microbiota-specific effector T-cells (TEFF) depends upon both the biology of the inducing bacteria and the specific site along the intestine where the microbe resides. Nonetheless, many of resident and epithelial cell adherent bacteria drive responses that are TH17 dominant. The TRM that develop from TH17 response in gut take up residence in the bone marrow, where E2 loss activates a subset of TRM to produce TNFα and IL-17A. The abundance of these TRM would dictate the amount of TNFα and IL-17A produced.

Modulation of T-cell responses to treat osteoporosis

If osteoporosis is induced by inflammation that is initiated by age and hormonal effects on T-cells, can these effects be reduced by restoring T-cell homeostasis? Is there a bone-specific feedback loop that can be engaged? Our laboratory was first to show that OC can present Ag derived from extracellular proteins on MHC class I. This ability, called cross-presentation, had been previously described only for specialized Ag presenting cells. Ag presentation by OC to CD8 T-cells induces FoxP3, CD25, IL-10, IL-2, IL-6 and RANKL in CD8 T-cells [89, 90]. FoxP3 and CD25 are markers of TcREG, regulatory T-cells that are immune suppressive. TcREG are short lived (half-life ~ 7 days) and rapidly induced (~12 hours). They are immunosuppressive after single Ag exposure to prevent and/or resolve inflammation locally [91–93]. OC-induced TcREG are also anti-inflammatory and immune suppressive[94]. Further, TcREG suppress OC, forming a negative feedback loop [91]. In contrast to TREG, TcREG do not senesce and become proinflammatory with age [94]. In the context of osteoporosis, we also showed that TcREG can be induced by pulsed, low-dose RANKL in vivo, reducing TNFα and IL-17A, and causing a bone anabolic effect in OVX mice [83]. Thus, TcREG induction leads to resolution of inflammation that consequently improves bone mass.

The effect of T-cell mediated inflammation on cells of the bone remodeling unit (BRU):

The long-standing paradigm for osteoporosis is that sex hormones directly regulate OC, OB and growth plate chondrocytes to maintain bone mass [95]. Experiments showed that E2 regulates the expression of FasL in osteoclasts and osteoblasts inducing apoptosis in osteoclasts to limit bone resorption in premenopausal women [96–99]. At the same time, E2 extends the lifespan of osteoblasts and osteocytes[96, 100, 101] to favor bone formation. Therefore, E2-loss leads to increased OC and concurrent decreased OB numbers, in line with the notion that E2 regulates the BRU directly. This paradigm has led to drug treatments for osteoporosis that have to-date focused on restoring the balance between bone resorption and formation by targeting cells in the BRU. For instance, antiresorptives such as bisphosphonates [102] and denosumab [103] (anti-RANKL antibody) suppress OC, whereas teriparatide[104] (PTH1–34) and romosozumab[105] (anti-sclerostin antibody) target OB. OC have received attention as targets of inflammation because they mediate bone and joint destruction in rheumatoid arthritis. However, the osteolineage cells, OB and osteocytes (Ocy) may also respond to inflammation. OB function is also important for bone quality and thus resilience to fractures. Ocy are important regulators of BRU, but little is understood about the impact of inflammation on Ocy. Thus, the imbalance in the BRU likely depends not only on the OC, but also on OB dysfunction or reprogramming of Ocy. Since therapy for established osteoporosis requires new bone formation, more exploration of the role of osteolineage cells as targets of inflammation is warranted.

Therapies for osteoporosis

Antiresorptive therapies (RANKL blockade or bisphosphonates) slow or stop the progression of osteoporosis[106–108]. However, antiresorptive therapies in postmenopausal women did not increase bone formation [109, 110] indicating that a deficit in OB activity remains. Although the underlying causes are not yet clear, anabolic therapies (e.g., teriparatide and romosozumab) seem to increase bone mass only for a limited period of time, and bone microarchitecture did not improve unless both antiresorptive and anabolic agents were combined in the SHOTZ clinical trial[111, 112]. None of the currently approved therapies for osteoporosis target the immune system because they are based on the presumption that E2 directly regulates the BRU. We posit that novel approaches to restore homeostasis are needed to optimally treat osteoporosis and other forms of bone loss. Resolution of inflammation is an active process that promotes tissue healing, restores function and homeostasis [113, 114] and thus is beneficial over blockade. Taking advantage of the OC-TcREG axis to resolve inflammation could provide a novel therapeutic approach to heal the bone and provide long-lasting prevention of osteoporotic fractures.

Summary

In conclusion, all mammals undergo age-related bone loss soon after achieving peak bone mass. There is a basal rate of decline, but environmental and lifestyle factors can increase or decrease the pace of bone loss. The underlying mechanism for the basal rate of bone loss is unknown. In this review, we propose that proinflammatory T-cells promote bone loss through three different mechanisms, two of which are common to both sexes and a third mechanism that is functional in perimenopausal and postmenopausal women with declining estrogen. Modulation of this T-cell inflammation via engagement of an OC- TcREG negative feedback loop restores bone homeostasis and holds therapeutic promise for the treatment of osteoporosis and other diseases with inflammatory bone loss.

Acknowldgements

We acknowledge the contribution of current and past members of the Aurora and Veis labs to the ideas presented in this review.

Grant Support:

This research was partially supported by NIH under Award Numbers: R01-AR070030 (DV), R01-AI161022 (DV) and P01-CA100730 (DV).

Footnotes

Declaration

The authors do not have existing conflict of interest.

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