Intermittent Methionine Restriction: A Superior Approach to Bone Health

Intermittent Methionine Restriction: A Superior Approach to Bone Health

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.”

Research Position Available

Dr. Sailendra Nichenametla’s lab at the Orentreich Foundation for the Advancement of Science (Cold Spring-on-Hudson, NY) is hiring a Senior Technician or a Senior Post-doctoral Fellow. Dr. Nichenametla investigates how Sulfur Amino Acid Restriction (SAAR, previously called Methionine Restriction) extends lifespan and confers metabolic benefits. The candidate will work on various SAAR-related projects associated with mechanisms, nutritional aspects, and prevention of diseases, including metabolic diseases, cancers, and proteostatic disorders. Responsibilities include generating data extensively from rodent models and occasionally from in vitro studies and clinical study specimens. Routine daily activities include performing experiments and data analysis, drafting publication-quality manuscripts, assisting in submitting grant proposals, and presenting work at scientific meetings.

Minimum Requirements:

Post-Doctoral Fellow

  • A Ph.D. with 2 years of post-doctoral experience.
  • Independent thinking (commensurate with career level).
  • Demonstrable research experience in biomedical sciences in two or more of the following areas/techniques: nutrition, aging, metabolism (tracer-based metabolic studies), animal colony management, cell culture, and molecular biology.
  • At least one paper as first author published during your post-doc position.
  • At least 1 year experience working with mice or rats.
  • Ability to draft publication-quality manuscripts.

Senior Technician

  • Ability to perform various assays related to the research areas mentioned above.
  • Ability to quickly learn new assays and develop new methods.
  • Excellent attention to detail.
  • Independent thinking (commensurate with career level).
  • Demonstrable research experience in biomedical sciences in two or more of the following areas/techniques: nutrition, aging, metabolism (tracer-based metabolic studies), animal colony management, cell culture, and molecular biology.
  • At least three to four publications demonstrating your contribution to data acquisition.
  • At least 1 year experience working with mice or rats.
  • Ability to write methods sections of manuscripts, laboratory protocols, etc.

Application Materials:

  • Cover letter.
  • Full curriculum vitae including education or other academic appointments, complete publication record, and research skills listed in detail.
  • PDF files of your previous research representing the qualifications of the position you are applying for.

Email your application materials to ofas@orentreich.org.

Sailendra Nichenametla Recipient of Inaugural Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience

Sailendra Nichenametla Recipient of Inaugural Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience

Senior Scientist Sailendra Nichenametla, Ph.D., has been named as a recipient of the inaugural Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience Research, presented by the American Federation for Aging Research (AFAR) and Hevolution Foundation. Eighteen three-year awards of US $375,000 each have been granted to support research projects in basic biology of aging or geroscience—a research paradigm based on addressing the biology of aging and age-related disease to promote healthy aging. Dr. Nichenametla will utilize the funds to investigate the role of serinogenesis in regulating lipid metabolism.

The inaugural awards support talented early career investigators at research institutions around the world, including Albert Einstein College of Medicine, Boston University School of Medicine, Mayo Clinic, and the University of Wisconsin-Madison.

“In partnership with AFAR, Hevolution Foundation is excited to strengthen the international pipeline of aging researchers through the New Investigators Awards,” shares Felipe Sierra, PhD, Chief Scientific Officer, Hevolution Foundation. “We want to help fill the void and speed the pace of scientific discovery on the processes of aging by dramatically increasing the research workforce. This initial round of grants is a significant step toward that goal.”

Recipients of the New Investigator Awards were selected through a rigorous, peer-review process. Applications were reviewed by established aging researchers who volunteer their time and expertise to select scientists and research projects that have the greatest likelihood of making significant contributions to help us stay healthier longer as we grow older.

To learn more about Dr. Nichenametla’s research, visit www.orentreich.org/nichenametla-lab. For more information on the Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience visit www.afar.org/funding-opportunities.

2022 OFAS Report of Directors

2022 OFAS Report of Directors

As the year comes to a close, we at the Orentreich Foundation for the Advancement of Science (OFAS) wish to thank our friends around the globe for their continued support. To view our recently published 2022 Report of the Director, click here.

We hope you will consider investing in OFAS’s research efforts with a donation. With each day that passes, advancements are made toward the goal of extending healthy lifespan, and each day OFAS is able to be a part of this work because of friends like you.

Thank you for your part in making OFAS’s 2022 such a success!

Sincerely,

David S. Orentreich, MD, FAAD
Director

2022 Norman Orentreich Award for Young Investigator on Aging

2022 Norman Orentreich Award for Young Investigator on Aging

OFAS presented the third Dr. Norman Orentreich Award for Young Investigator on Aging to Maximilian Schmid-Siegel, a Ph.D. candidate at the Medical University of Vienna Institute of Medical Genetics (Vienna, Austria). The award was presented at the 15th International Symposium on Neurobiology and Neuroendocrinology of Aging, Bregenz, Austria. Maximillian was selected for his presentation “Ribosome heterogeneity by rRNA methylation in skin cell senescence”.

This award is intended to inspire young investigators to continue aging research and to acknowledge the potential of their work. In addition to the US$1,000 prize, Max was invited to present at the 2023 OFAS Symposium on Healthy Aging.

 

Symposium organizer Holly Brown-Borg, recipient Maximillian Schmid-Siegel, OFAS Deputy Director of Research Jay Zimmerman.

 

An intermittent form of methionine restriction protects against obesity and may extend lifespan

An intermittent form of methionine restriction protects against obesity and may extend lifespan

An intermittent variation of the dietary intervention methionine restriction protects against obesity and provides additional metabolic health benefits to mice, according to a study from the Johnson Laboratory, recently published in Aging Cell.

The results of this work are important in that they suggest that a limited period of dietary intervention (i.e., only three days per week) may be sufficient to produce the anti-aging effects associated with continuous methionine restriction. Such an approach could allow people to eat as normal for the majority of the week, but still receive the health benefits described for continuous methionine restriction.

Methionine restriction has been shown to protect rodents against diet-induced obesity and can extend their healthy lifespan by up to 45%. Promisingly, recent studies have suggested that the effects of methionine restriction on health and lifespan are likely to be conserved in humans. Given that the vegan diet is low in total protein and amino acids, methionine restriction is possible for people. However, such a diet might not be practicable or desirable for everyone.

As a result, the Johnson Laboratory sought to develop a version of methionine restriction that produces the same benefits as the continuous intervention, while also being more convenient and easier to perform. They were inspired by published reports that intermittent forms of other health-promoting interventions (i.e., the ketogenic diet and calorie restriction) are similarly effective to their continuous counterparts.

The team first tested whether two increasingly stringent versions of intermittent methionine restriction offered the same protection against obesity as the continuous intervention. They fed male mice one of four high-fat diets: 1) a control diet containing typical amounts of methionine, 2) a continuously methionine-restricted diet, 3) a diet containing typical amounts of methionine for four days, followed by a methionine-restricted diet for three days, and 4) a diet containing typical amounts of methionine for four days, followed by a diet completely lacking methionine for three days. The authors found that the more stringent of the two forms of intermittent methionine restriction was just as effective as the continuous intervention in protecting against the dramatic weight gain and fat accumulation seen in mice fed the high-fat control diet. Similarly, the authors observed that intermittent methionine restriction also completely protected female mice against diet-induced obesity.

Next, they explored the effects of intermittent methionine restriction on physiological changes that normally result from continuous methionine restriction. For this purpose, they measured the levels of four metabolic markers (the hormones IGF-1, adiponectin, leptin, and FGF-21) in blood samples from previously treated mice. As expected, they found that intermittent methionine restriction resulted in changes similar to those of continuous methionine restriction. This finding is particularly interesting given that a body of evidence suggests that low IGF-1 levels are associated with an extension of healthy lifespan. So, it is likely that intermittent methionine restriction will produce an extension of lifespan similar to what has previously been observed for continuous methionine restriction.

An image showing the comparative effects of continuous methionine restriction and intermittent methionine restriction in rodents on outcomes for obesity, hepatosteatosis, and dysglycemia.

Continuous methionine restriction (MR) extends the healthy lifespan of a number of model organisms, including rodents. A novel intervention featuring only three days of stringent MR per week (aka, intermittent MR; IMR) protects mice against diet-induced obesity, fatty liver (aka, hepatosteatosis), and dysregulation of blood sugar (aka, dysglycemia). It also produces beneficial changes in the levels of multiple energy-sensing and longevity-regulating hormones. As a result, IMR is likely a preferable health-promoting strategy to continuous MR.

“This is a very exciting result and actually one of the more significant findings to come from the Orentreich Foundation in recent years” notes senior author Dr. Jay Johnson, an Associate Research Scientist at OFAS. “In addition to protecting mice against diet-induced weight gain, intermittent MR also guards against the development of both fatty liver and dysglycemia. In fact, intermittent MR is actually more effective at maintaining normal blood sugar than classical MR … and this despite four fewer days of dietary intervention per week. Interestingly, mice undergoing intermittent MR also retain more of their lean body mass as compared with their continuously methionine-restricted counterparts. As a result, we consider intermittent MR to be a superior alternative to the classical intervention, and we hope that many of the benefits that it confers to mice will also hold true for humans.”

To view the article, published in Aging Cell, visit https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13629.