The Bones Are Talking. Is Your Lifespan Listening?

The bones of our body, long regarded as silent frameworks, have emerged as active participants in the regulation of human health and aging. They do more than support movement or protect vital organs. They produce hormones, respond to signals from distant organs, and influence longevity at the molecular level.

Bone as an Endocrine Organ

One of the most important discoveries in recent decades is that bones are endocrine organs. They secrete hormones that act far beyond the skeleton. Osteocalcin, a hormone secreted by osteoblasts, was once thought to be involved solely in bone mineralization. It is now recognized as a regulator of energy metabolism, cognitive function, and fertility. In mice, injections of osteocalcin in old age improve insulin sensitivity, enhance memory performance, and increase exercise capacity. Its levels decline with age, and this decline is associated with reduced metabolic efficiency and cognitive performance.

Fibroblast growth factor 23 (FGF23), another bone-derived hormone, controls phosphate homeostasis. It acts primarily on the kidneys to regulate phosphate excretion and vitamin D metabolism. To function properly, FGF23 requires a co-receptor called α-Klotho. α-Klotho, predominantly produced in the kidneys and brain, has been shown to extend lifespan in mice when overexpressed. In humans, certain Klotho gene variants correlate with increased longevity and cognitive preservation in older age.

The Role of Hormones in Aging

These bone-derived hormones interact with other systems that regulate aging. Osteocalcin influences insulin secretion by the pancreas and affects neurotransmitter synthesis in the brain. FGF23 and Klotho help maintain mineral balance and protect against vascular calcification. Loss of their regulatory functions is linked to age-associated conditions such as cardiovascular disease, frailty, and cognitive decline.

Some hormones that act on bone, such as growth hormone (GH) and insulin-like growth factor 1 (IGF-1), also play a role in the aging process. While GH and IGF-1 promote bone growth and muscle maintenance, excessive activity in these pathways has been linked to increased cancer risk and accelerated aging. Interestingly, individuals with Laron syndrome, who have mutations that reduce GH receptor function, are resistant to cancer and diabetes and may experience longer lifespans.

Immune and Marrow Aging

Bones are also central to immune regulation. The bone marrow is the site of hematopoiesis, the formation of immune cells. With aging, this process becomes dysregulated. Inflammatory signals increase, stem cell function declines, and immune output becomes imbalanced. The result is immunosenescence—a state of reduced immune competence. This decline in immune health is interlinked with changes in bone metabolism and the hormones secreted by bone cells.

Research is uncovering how interventions that modulate bone-derived hormones could improve systemic aging. Caloric restriction, physical activity, and compounds like rapamycin and senolytics are under investigation for their ability to preserve or restore youthful patterns of hormone secretion. In animal models, senolytics that remove senescent cells from tissues have been shown to increase circulating levels of Klotho and improve skeletal health.

Sex Hormones and Skeletal Aging

The loss of sex hormones, particularly in postmenopausal women, accelerates skeletal aging. Estrogen maintains bone density and influences the production of osteocalcin and other local signaling molecules. After menopause, the decline in estrogen contributes to osteoporosis, but it also affects cardiovascular function, metabolic balance, and neuroprotection. Hormone replacement therapies and emerging interventions targeting reproductive aging are being studied not only for their effects on fertility but for their potential to preserve systemic hormonal homeostasis.

Toward Therapeutic Targeting of Bone Hormones

A growing number of clinical trials are exploring therapies that target bone-derived hormones. Whether through recombinant forms, gene therapy, or upstream regulation via exercise or pharmacology, the goal is to extend healthspan by maintaining the regulatory functions these hormones perform. Unlike traditional treatments for osteoporosis that focus only on bone density, these approaches recognize that bone health is intertwined with brain function, metabolism, and immunity.

The recognition of bone as a hormonal organ has shifted how scientists understand aging. As researchers continue to map these hormonal pathways, new strategies for extending healthy human life may emerge from the very structures that have supported us since birth. Bones are no longer passive. They are active regulators of aging. And the better we understand their influence, the better equipped we are to live longer, healthier lives.

References

1. Du Y, et al. Endocrine Regulation of Extra‑skeletal Organs by Bone‑Derived Factors. Aging (Albany NY). 2021;13(3):290‑309. DOI: 10.18632/aging.202013. This review details osteocalcin and FGF23 endocrine roles in systemic metabolism and cognition. https://doi.org/10.3389/fcell.2021.778015
2. Han Y, et al. Paracrine and endocrine actions of bone—the functions of secretory proteins from bone cells. Bone Research. 2018;6:16. DOI: 10.1038/s41413-018-0019-6. Covers osteocalcin, FGF23, and lipocalin‑2 roles in whole‑body physiology. https://www.nature.com/articles/s41413-018-0019-6
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