DECREASED BONE DENSITY AND PROGRESSIVE COGNITIVE DECLINE WITH AGEING: THE ROLE OF PHYSICAL EXERCISE

G. Cerulli¹, P.P. Ciampa^2*, M.J. Conti³, G. Barassi⁴, A. Coppola⁵, C. Genovesi⁶ and G. Tetè^7*

¹ Istituto di Ricerca Traslazionale per l’Apparato Locomotore “Nicola Cerulli”, Perugia, Italy;
² Department of Anatomical, Histological and Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Rome, Italy;
³ Faculty of Medicine, S. Andrea University “La Sapienza”, Rome, Italy;
⁴ Center for Physiotherapy, Rehabilitation and Re-Education (Ce.Fi.R.R.) Venue “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy;
⁵ Private Practice, Studio Armando Coppola, Corso Garibaldi 246, 80141 Naples, Italy;
⁶ Skin Centres, Private Practice, Avezzano-Pescara, Italy;
⁷ “Sustainable Blue Economy and One Health”-XL Cycle, Department of Human Sciences, Law, and Economics, “Leonardo da Vinci,” UNIDAV, Telematic University, Chieti, Torrevecchia Teatina, Italy.

*Correspondence to:
Giulia Tetè,
“Sustainable Blue Economy and One Health”-XL Cycle,
Department of Human Sciences, Law, and Economics,
“Leonardo da Vinci,” UNIDAV, Telematic University, Chieti,
Torrevecchia Teatina, Italy
e-mail: tetegiulia92@gmail.com

Received: 26 January, 2026 Accepted: 20 March, 2026

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2026 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Ageing leads to decreased bone density and progressive cognitive decline due to cellular and molecular changes in the body. Physical activity can slow ageing and improve cognitive function in the brain. Bone, formed by osteoblasts, osteoclasts, and osteocytes, is continuously renewed and maintains bone homeostasis. In ageing, bone resorption exceeds bone formation, resulting in bone loss and subsequent osteoporosis and fractures. With age, osteoclasts resorb more bone, while osteoblasts form less, hormone production declines, physical activity decreases, calcium absorption declines, and low-grade chronic inflammation mediated by inflammatory cytokines sets in. Physical activity stimulates the formation of new bone, increases muscle strength which protects bones, and improves both physical and mental health. With ageing, the receptor activator of nuclear factor κB ligand (RANKL) stimulates osteoclasts, while osteoprotegerin (OPG) inhibits it. RANKL activates the formation of osteoclasts, which are responsible for bone resorption, while OPG inhibits osteoclasts and regulates bone remodelling. The RANKL/RANK binding recruits tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), activating transcription factors such as NF-κB, c-Fos, and the master transcription factor, NFATc1. NFATc1 does not directly stimulate bone formation but regulates the resorption phase of bone remodelling. Ageing causes a decline in neurotransmitters such as dopamine, acetylcholine, and serotonin, resulting in reduced cognitive performance. Physical activity positively influences both bone and brain ageing through mechanical, metabolic, and molecular mechanisms. In conclusion, ageing leads to a decline in bone mass and cognitive performance, which can be improved through physical activity.

KEYWORDS: Ageing, bone density, brain, cognitive function, exercise

INTRODUCTION

Decreased bone density and reduced brain activity are processes related to ageing that result from cellular and molecular changes affecting metabolism, neuronal activity, inflammation, and hormone production (1). Physical activity can slow these changes that occur with ageing (2).

A large number of published articles report that sports and physical activity can slow the ageing process that occurs in the bones and brain (3). The age-related decline in bone density results from bone remodelling, a dynamic balance between bone formation and resorption (4). Bone is a dynamic tissue that is continuously renewed by osteoblasts, osteoclasts, and osteocytes (5). Osteoblasts are the cells responsible for the formation of new bone. They derive from mesenchymal stem cells in the bone marrow and play an important role in bone tissue repair (6). Osteoclasts are cells specialised in bone tissue degradation (bone resorption) where they degrade bone by dissolving the mineral component, creating a closed zone on the bone surface, and pumping hydrogen ions (7).  This lowers the pH and dissolves hydroxyapatite crystals (8).  Additionally, osteoclasts play a key role in the degradation of the organic matrix by producing proteolytic enzymes such as cathepsin K and metalloproteinases that degrade type I collagen and other proteins (9).  Osteocytes are mature bone cells derived from osteoblasts and represent approximately 93% of bone tissue cells. Their main function is to maintain and regulate bone tissue by regulating the exchange of calcium, phosphate, and other minerals, contributing to bone homeostasis (10).

DISCUSSION

During ageing, bone resorption exceeds bone formation, causing bone loss and the development of osteoporosis, a skeletal disease characterised by a reduction in bone mineral density and alterations in bone microarchitecture, making bones more fragile and prone to fracture (11).  Osteoporosis involves progressive bone loss; osteoclasts resorb more bone, and osteoblasts form less (12). With age, there is reduced hormone production, physical activity, and absorption of calcium and vitamin D, and bone density tends to decrease, making bones more fragile and more likely to fracture (13). Physical activity stimulates the formation of new bone tissue, increases muscle strength, which protects bones, and improves balance and reduces falls (14).

The main molecular pathways involved in bone density decline with ageing are the RANK/RANKL/OPG system, where receptor activator of nuclear factor κB ligand (RANKL) stimulates osteoclasts and osteoprotegerin (OPG) inhibits them (15). RANKL is an important protein in regulating bone remodelling. It belongs to the cytokine family and is produced by various cells, such as certain immune system cells, osteoblasts, osteocytes, and bone marrow stromal cells (16).

RANKL activates the formation of osteoclasts responsible for bone resorption. RANKL binds to its receptor, RANK, present on osteoclast precursors and activates the NF-κB pathway, resulting in the subsequent differentiation of precursors into mature osteoclasts and increased bone resorption (17).

OPG is an important glycoprotein in regulating bone remodelling because it inhibits osteoclast formation, reducing bone resorption (18). This molecule also belongs to the tumor necrosis factor (TNF) receptor family and is primarily produced by bone marrow stromal cells, endothelial cells, osteoblasts, and osteocytes. OPG’s function is to block osteoclast activation through the decoy receptor (19).

In bone metabolism, OPG binds to RANKL, preventing it from binding to RANK, an effect that reduces osteoclast formation and bone resorption (20).  Physiologically, OPG maintains the balance between bone formation and resorption. During ageing, RANKL increases and OPG decreases, which leads to increased bone resorption and a decrease in a series of hormones such as growth hormone, insulin-like growth factor 1 (IGF-1), estrogen, and testosterone, with a reduction in bone formation (21). Ageing occurs with low-grade chronic inflammation, with increased pro-inflammatory cytokines such as IL-1, TNF, and IL-6 (22). These cytokines activate osteoclasts by increasing the RANK/RANKL system, the main molecular mechanism of osteoclastogenesis (23).

The RANKL/RANK binding recruits TNF receptor-associated factor 6 (TRAF6), activating transcription factors and the NF-κB, c-Fos, and NFATc1, the main transcription factor that is the “master regulator” of osteoclast differentiation (24). TRAF6 is a determinant signalling adaptor protein in bone metabolism, especially in osteoclast differentiation during bone remodelling (25). TRAF6 is involved in both osteoclastogenesis and osteogenesis (26). Indeed, bone remodelling depends on the balance between bone-forming osteoblasts and osteoclasts, which are responsible for bone resorption.

NFATc1 does not directly stimulate bone formation but regulates the resorption portion of bone remodelling. NFATc1 is essential for osteoclast differentiation, and without this molecule, monocyte/macrophage precursors do not transform into osteoclasts (27). NFATc1 activation occurs with the formation of NF-kB and c-Fos, which induce the expression of NFATc1, which becomes the master regulator of osteoclast differentiation (28).  NFATc1 activates genes for osteoclast function, such as cathepsin K, which degrades bone matrix, and TRAP, an osteoclast marker. In the nucleus, NFATc1 activates calcitonin receptor genes required for osteoclast formation and function (29). Calcitonin is a hormone produced by thyroid C cells involved in bone metabolism, primarily by inhibiting osteoclast activity and, therefore, bone resorption. It does not directly stimulate osteogenesis, but it reduces bone loss (30). The calcitonin receptor is the receptor through which calcitonin exerts its effects on bone tissue (31). The calcitonin receptor is expressed primarily on mature osteoclasts and mediates calcitonin’s inhibition of bone resorption.

In osteoblasts, IL-1 increases RANKL expression, enhances the activity of mature osteoclasts, and reduces OPG production. TNF stimulates RANKL production (even when RANKL levels are low) and directly activates NF-κB in osteoclast precursors. IL-6 acts through gp130 and increases RANKL production (12).

During ageing, the brain undergoes structural and functional changes, resulting in a reduction in brain function, including synaptic loss or reduction, reduced neuronal plasticity, decreased neurogenesis (most notably in the hippocampus), mitochondrial dysfunction, and oxidative stress (32).  Ageing also results in a reduction in neurotrophic factors such as brain-derived neurotrophic factor (BDNF), impaired memory (33), and a decline in neurotransmitters such as dopamine, acetylcholine, and serotonin, resulting in a reduction in cognitive speed (34).

Physical activity during ageing affects both the bones and the brain through mechanical, metabolic, and molecular mechanisms (35).  Mechanical stimulation of the bones activates osteocytes, which produce osteoblasts (36). Exercise increases growth hormone, testosterone, and insulin sensitivity, effects that lead to improved bone metabolism (37). Physical activity also affects the brain by increasing neurotrophic factors, including increased levels of vascular endothelial growth factor (VEGF), IGF-1, and BDNF, resulting in increased neurogenesis, memory, and synaptic plasticity. Furthermore, vascularization is improved, and aerobic activity increases cerebral blood flow and cerebral angiogenesis (38). Exercise reduces levels of pro-inflammatory cytokines and increases the production of anti-inflammatory ones such as IL-10 (39).

CONCLUSIONS

In conclusion, it can certainly be stated that ageing results in low-grade inflammation, with loss of bone density, imbalanced bone remodelling, reduced brain activity, and decreased neuronal plasticity. Exercise stimulates osteoblasts and bone formation, increases neurotrophic factors, improves metabolism, and reduces inflammation, resulting in improved physical, skeletal, and cognitive functions.

Conflict of interest

The authors declare that they have no conflict of interest.

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