An intermittently methionine-restricted diet reduces marrow fat accumulation and preserves more bone mass than continuous methionine restriction, according to a recent study from the Johnson Lab published in Aging Biology.

Methionine restriction (MR) is known to increase the lifespan of multiple species, with an increase of up to 45% observed in rodents. The believed mechanism behind this benefit is the lowering of the hormone IGF-1. In addition to increasing lifespan, MR has also been shown to confer a variety of health benefits. These primarily include protection against metabolic dysregulation, such as obesity, dysglycemia, hyperlipidemia, and hepatosteatosis.

Although the numerous positive benefits of continuous MR outweigh its drawbacks, there are some detrimental effects of this intervention. First, maintaining the exceedingly low levels of dietary methionine required for long-term continuous MR would be challenging, if not impossible, for individuals outside of a controlled laboratory setting. Furthermore, previous studies conducted at OFAS have shown that MR can negatively affect the development of the musculoskeletal system. Specifically, it has been found to impair whole-body growth in mice, leading to reduced maintenance of lean muscle mass and the development of bones that are less dense and more frail.

Research from the Johnson Lab has aimed to address the challenges posed by continuous MR by developing an intermittent methionine restriction (IMR) regimen. Unlike continuous MR, which necessitates a diet continually low in methionine, IMR produces the same benefits but requires only three days of intervention each week (Fig. 1). Designed to make methionine restriction more feasible, the group’s prior studies have shown that IMR provides all of the short-term benefits of continuous MR without compromising lean body mass development. The group’s latest publication investigates whether IMR can also circumvent the adverse effects of continuous MR on bone composition and structural integrity.

Fig. 1: Graphical representation of continuous MR as compared to intermittent MR. Red circles on the calendar indicate days when methionine is restricted.

Intermittent MR Improves Bone Quality

Trabecular bone, also known as spongy bone, features a porous, honeycomb-like structure that provides strength and flexibility. It is primarily located at the ends of long bones and the inner layers of most bones. Cortical bone, or compact bone, on the other hand, is dense and rigid, forming the hard outer layer of bones and providing structural support and protection. In mice, continuous MR is known to impair the formation of both trabecular and cortical bone. In contrast, mice undergoing an IMR regimen do not experience impairment in these types of bone (Fig. 2 and 3).

Fig. 2: Comparison of micro-computerized tomography images of trabeculae from mice treated with continuous MR (MR) and intermittent MR (IMR). Note that MR trabeculae have less bone and greater space in their lattice-like structure. IMR trabeculae have thickness and spacing more similar to that of the control (CF).

Fig. 3: Images depict micro-computerized tomography images of halved femoral head sections. Note that the trabeculae (lattice-like structure comprising the inner region) of continuously methionine-restricted mice (MR) are fewer and more dispersed than that of intermittently methionine-restricted (IMR) counterparts. Also of note, the cortical bone (solid bone around the periphery) of IMR femurs is thicker and more similar to that of the control (CF).

The impairment in the bones of mice under continuous MR is driven by a decrease in bone-producing osteoblasts and an increase in bone-degrading osteoclasts, leading to greater bone resorption and reduced bone formation. In contrast, IMR showed a substantial increase in osteoblasts compared to continuous MR. Despite a similar increase in osteoclasts, the significant rise in osteoblasts with IMR allows for compensatory maintenance of bone formation.

The study also found significant changes in the central cavity of the bone, particularly in marrow fat production through adipogenesis—a process influenced by age, diet, and disease, and linked to bone health and metabolic regulation. IMR significantly reduced marrow fat accumulation compared to continuous MR, suggesting IMR’s potential in preventing the decline in bone health associated with adipogenesis.

Understanding whether these structural changes translated to increased strength was particularly important. Accordingly, direct mechanical strength testing revealed that continuous MR weakened bones, whereas IMR preserved bone strength.

According to the authors, the significance of this study is notable. Contributing author Jason Plummer states, “One focus of our lab’s recent work is to enhance the translation of MR and allow for its benefits to be applied in everyday life. In our previous study, the design of an intermittent methionine-restricted diet achieved a more convenient means of methionine restriction while still sustaining lean body mass. This most recent study demonstrates that intermittent MR also has a similar effect in the preservation of bone structure while maintaining the robust health benefits of continuous MR.” The conservation of these particular physical qualities is especially important in pro-longevity interventions. The author further states, “The loss of lean muscle mass and bone are both well-known and debilitating aspects of aging. Any intervention that promotes longevity but exacerbates those aspects would be highly problematic.”