What Causes Bone Loss With Age? A Look at How Depleted Stem Cell Pools Cause Bone Breakdown, and How NMN Can Rescue It
Imagine your bones being so weak and brittle that simple movements like coughing or bumping into a table could break them — this can be the reality for about one-third of adults upon reaching their 80s. Despite bones seeming to be static and unmoving entities, our bones are actually living tissue that is continually being broken down and replaced by healthier bone cells. But, many older adults have declining function in these processes, making them susceptible to severe bone loss that significantly affects their day-to-day activities and quality of life.
As age-related bone deterioration places a heavy physical, mental, and financial burden on patients, caregivers, and healthcare facilities, many researchers have prioritized uncovering why this bone loss occurs in the first place — and how to prevent it. In a recent study published in the journal Aging Cell, Hu and colleagues out of Tianjin Medical University in Tianjin, China, show how one gene family known as NAP plays a vital role in the bone breakdown saga — and how the compound NMN (nicotinamide mononucleotide) can step in to help.
The Internal Battle of Bone Building Vs. Breakdown
While many factors contribute to skeletal aging and bone loss, the reduced regenerative abilities of specific cells called bone marrow mesenchymal stem cells (BMSCs) may be a leading cause. These unique adult stem cells are found in the bone marrow and act as building blocks for skeletal tissue, as they can develop into bone cells called osteoblasts.
Throughout life, our bodies maintain bone integrity by a process known as bone remodeling, involving cells called osteoclasts and osteoblasts. Osteoclasts work to absorb and remove older bone, allowing for the development of new bone by osteoblast cells — a process known as osteogenesis. With age, osteoblast numbers decline, leading to excessive bone removal without enough new osteogenic growth.
BMSCs have the potential for self-renewal, thereby serving as a lifelong reservoir for creating new osteoblasts. However, the quality and quantity of available stem cells in this pool decrease with age, likely due to increased senescence — when cells undergo an irreversible growth arrest that renders them dysfunctional and creates inflammation in surrounding cells.
This increase in BMSC senescence significantly limits their potential in regenerating bone cells, which is why researchers look for ways to halt senescence as a tool for slowing bone breakdown. But, researchers still aren’t entirely sure why excessive BMSC senescence occurs in the first place, which is what this study aimed to uncover.
Uncovering the Genes That Generate Bone Loss
Previous research has found that the gene family NAP is involved in cell proliferation and the maturation of other types of stem cells. Also known as nucleosome associate proteins, NAPs work by changing the organization of DNA to control gene activity. This knowledge led Hu and colleagues to speculate that NAP — specifically, one family member called NAP1L2 — also plays a role in controlling BMSC activity.
To test their theory, the China-based research team looked at BMSC gene expression profiles. Gene expression is the process of our bodies encoding genetic information (DNA) into parts we can use, like proteins. Not all of our cells express every gene simultaneously and in the same amounts — this would be chaotic and highly demanding of energy. Instead, our cells respond to signals to decide when and how much of a gene to express at any one time. As we grow older, genetic expression can alter dramatically, leading to physiological symptoms of aging and disease.
In this study, Hu and colleagues pinpointed NAP1L2 as a gene with highly elevated expression in aging humans, mice, and cells. In both older adults with bone loss and 24-month-old mice (about 70 in humans), elevated NAP1L2 expression correlated with low bone mineral density and loss of bone strength. To ensure that NAP1L2 was the underlying reason for these correlations, they looked at mice that didn’t express any NAP1L2, finding that they had sufficient bone growth and delayed senescence. In contrast, mice with overly expressed NAP1L2 showed the opposite.
They also looked at how NAP1L2 affected BMSCs. Compared to cells from healthy young people, BMSCs from older (age 65 to 91) donors had significantly higher expression of NAP1L2 and senescence-related genes. The BMSCs of older adults exhibited growth arrest in the cell cycle, indicating that these cells could not go on to create bone-building osteoblasts. The older BMSCs also showed an accumulation of DNA damage and low mineralization of the extracellular matrix — a complex and dynamic network of structural support compounds that induce osteoblast production.
NMN Ameliorates Age-Related Bone Breakdown
From there, Hu and colleagues wondered if there was a way to mitigate NAP1L2’s bone-degrading qualities using NMN. NMN, or nicotinamide mononucleotide, is a precursor to nicotinamide adenine dinucleotide (NAD+) — a vital molecule necessary for proper cell function, energy production, and regulation of the aging process, including osteogenic abilities.
They found that adding NMN to the cells significantly suppressed NAP1L2 activity, which alleviated DNA damage and postponed the progression of senescent cells and their subsequent inflammatory damage. Essentially, the NAD+ precursor rescued the detrimental effects of overexpressed NAP1L2 on bone growth and restored osteogenic gene activity. However, the research team did not look at the effects of NMN in humans or mice, so more studies are needed to determine how it would play out in a clinical setting of bone loss.
All in all, these results demonstrate a close relationship between age-related bone loss and overexpression of NAP1L2, and that suppressing the gene’s activity with compounds like NMN may be beneficial for supporting bone health with age. As the inability of BMSCs to regenerate properly is implicated in many other age-related diseases, ranging from neurological to metabolic, this study suggests that NMN — or other methods to lower NAP1L2 activity — may be a promising therapeutic option for supporting more than just bone health.
As the authors conclude in their paper, “The translational merit of our study is to indicate that the aging antagonist reagent nicotinamide mononucleotide (NMN) has an inhibitory effect on NAP1L2 expression, thus providing a theoretical basis for the management of age-related diseases.”
References:
Hu M, Xing L, Zhang L, et al. NAP1L2 drives mesenchymal stem cell senescence and suppresses osteogenic differentiation. Aging Cell. 2022;e13551. doi:10.1111/acel.13551