Oxytocin’s Role in Managing Age-Related Muscle Decline and Body Fat Changes

Introduction

Aging is often accompanied by a myriad of physical and biological changes, some of which can be managed with medicine, while others remain less understood. One particularly puzzling aspect of aging that continues to perplex medical professionals is the alteration in body composition, specifically the changes in fat distribution and muscle mass. Many older adults may experience a combination of increased body fat and reduced muscle strength. This phenomenon, known as sarcopenic obesity, poses a significant challenge in geriatric health.

This narrative review article focuses on a novel approach to addressing sarcopenic obesity, optimizing muscle maintenance and regeneration, and improving body composition through the administration of oxytocin. Known for its role in social bonding and emotional connections, recent studies suggest that oxytocin significantly influences muscle maintenance and fat metabolism. The natural decline of oxytocin levels in aging individuals is thought to play a role in the development of sarcopenic obesity. By exploring the potential of oxytocin supplementation, this review aims to uncover its capacity to reverse these age-related changes. It will focus on the physiological mechanisms involved and its potential to enhance the overall health and body composition of older adults.

What is Sarcopenic Obesity?

Muscle mass typically begins to decline in the third decade of life, contributing to age-related decreases in strength and functional ability [1]. This progressive loss of muscle mass and strength, known as sarcopenia, often leads to a reduction in physical activity levels. Consequently, the decrease in physical activity can result in a positive energy balance and subsequent adipose tissue accumulation, fostering a sedentary lifestyle. This combination of reduced muscle mass and increased adiposity often culminates in a condition known as sarcopenic obesity. The interplay between sarcopenia and obesity can create a vicious cycle, where diminished muscle function and increased fat mass exacerbate each other, further impairing mobility and metabolic health [2].

Sarcopenic obesity is defined by the coexistence of sarcopenia (the loss of muscle mass and strength) and obesity (excessive body fat). It affects approximately 18% of older women and 40% of older men [2]. Despite its prevalence among the elderly, there is significant debate regarding the recommendation of weight loss as a treatment. The central concern is that weight loss interventions might not only reduce fat mass but also lead to a decrease in lean muscle and bone mass. This could potentially aggravate sarcopenia, a serious concern for older adults who are already at increased risk of becoming frail and debilitated [3]. Consequently, treating sarcopenic obesity effectively remains a complex and challenging task.

What are the Underlying Mechanisms of Sarcopenic Obesity?

Sarcopenic obesity is likely influenced by various factors, both biological and environmental. In this review, we will focus on the biological (or physiological) bases of sarcopenic obesity.

Protein Turnover

As we age, our bodies undergo significant changes in how they metabolize proteins. One process particularly affected by age is protein turnover.

Protein turnover in muscles involves an ongoing cycle of protein synthesis (creating new proteins) and protein degradation (breaking down old or damaged proteins). This process can be likened to farming, where farmers clear out aged crops and plant new ones. As we age, the rate of protein synthesis in muscle cells often declines, resulting in reduced production of new proteins for muscle growth and repair. Concurrently, there's an increase in the breakdown of existing muscle proteins. This imbalance leads to a negative protein balance, where muscle protein breakdown outpaces its replacement, ultimately causing muscle mass loss associated with sarcopenic obesity.

Researchers have found that the changes in protein synthesis and breakdown rates may be linked to age-related shifts in nutrition and hormonal balance [5]. Muscle protein synthesis is boosted by consuming protein-rich meals, owing to essential amino acids in our diet. Proteins consist of amino acids, with 20 different types forming a variety of proteins essential for bodily functions. Of these, 11 amino acids are naturally produced by the body, while the remaining nine, the 'essential amino acids,' must be obtained from food [6]. Certain amino acids, like leucine, are particularly effective in stimulating muscle protein synthesis.

Researchers have highlighted the importance of dietary protein, but the process of consuming and metabolizing protein becomes more complex with age. As we age, several factors contribute to less efficient protein utilization including a reduced intake of protein, a diminished ability to digest and absorb nutrients, inefficient transport of proteins from the gut to the bloodstream, and decreased uptake of amino acids by muscle cells. All of these factors can contribute to lower protein levels in the body and, ultimately, to the development of sarcopenia.

Researchers have highlighted the importance of dietary protein, but the process of consuming and metabolizing protein becomes more complex with age. Several factors contribute to less efficient protein utilization in older adults, including reduced protein intake, diminished ability to digest and absorb nutrients, inefficient transport of proteins from the gut to the bloodstream, and decreased uptake of amino acids by muscle cells. These inefficiencies can lead to lower protein levels in the body, exacerbating the loss of muscle mass and contributing to the development of sarcopenia and sarcopenic obesity.

To understand these processes better, we need to explore a specific mechanism involving the mTOR pathway. The mTOR pathway plays a critical role in regulating muscle protein synthesis and is central to the concept of anabolic resistance that occurs with aging.

The Role of mTOR Pathways in Anabolic Resistance and Muscle Health in Aging

As detailed in "Rapamycin Research and Clinical Trials: A Synthesis of Recent Scientific Findings," the mechanistic target of rapamycin (mTOR) is a critical complex that regulates various cellular processes, including growth, survival, and energy utilization. mTOR acts as a central control hub, interpreting environmental signals such as nutrient availability, energy status, and growth factors, and then issuing directives to cells accordingly [8].

In our youth, mTOR is essential for cell growth, protein synthesis, and overall anabolic processes. mTOR is particularly sensitive to certain amino acids, such as leucine and methionine, which can activate this pathway and promote muscle protein synthesis. For example, when a young athlete consumes a protein-rich meal containing leucine and methionine, these amino acids trigger mTOR activation, leading to increased muscle growth and strength as the body efficiently utilizes the nutrients for anabolic processes.

However, with aging, mTOR becomes overactive, even in the absence of optimal nutrient signals. This chronic hyperactivity of mTOR can lead to physiological changes that accelerate the aging process, including impaired muscle regeneration and increased cellular stress. This hyperactivity contributes to the accumulation of senescent cells, heightened inflammation, and is a root cause of many age-related chronic diseases. It also plays a potentially significant role in anabolic resistance.

It is well established that as we age, our bodies become ‘anabolic resistant,’ a condition where the ability to build new muscle protein in response to anabolic stimuli like resistance exercise or protein intake diminishes. The precise molecular mechanisms underlying anabolic resistance are not fully understood, but they represent a significant barrier to maintaining muscle mass and function in the elderly.

One prevailing theory is that chronic elevation of mTOR activity in aging may lead to anabolic resistance. As individuals age, the machinery controlling cellular growth may be at maximal capacity due to persistently high mTOR signaling, rendering cells less responsive to additional anabolic signals from protein intake or exercise. An older adult might consume the same protein-rich meal, but their overactive mTOR may not respond effectively to the nutrient signals, resulting in diminished muscle synthesis and strength gains—they become mTOR insensitive to anabolic stimuli. It is thought that this hyperactivity may contribute to age-related changes in muscle strength and functionality, suggesting mTOR's pivotal role in the aging phenotype.

Recent evidence from the Laboratory of Prof. David Glass has observed a linear increase in the basal (fasted) activity of RPS6, a downstream target of mTOR, across the lifespan. This finding indicates that mTOR signaling remains elevated even in a fasted state in older individuals [18].

Notably, the same study administered an mTOR inhibitor similar to rapamycin for six weeks, resulting in the restoration of mTOR signaling intermediates and the reversal of sarcopenia. These results suggest that pharmacological modulation of mTOR activity could restore its function to more youthful levels, potentially alleviating age-related anabolic resistance and improving muscle health [18].

Therefore, if mTOR is chronically activated in a basal, rested state, it cannot be further activated in response to protein intake and/or exercise. This implies that mTOR activity may need to be modulated and restored to ‘youthful’ levels through pharmacological therapies, such as rapamycin, to overcome anabolic resistance and improve muscle protein synthesis in the elderly.

We don’t think of these pathways in isolation, however. While the mTOR pathway is a key switch of anabolic activity, it is one player in an orchestra of metabolic pathways that may be a contributor to anabolic resistance. Let’s now take a closer look at the role of muscle stem cell dysfunction in anabolic resistance.

The Decline of Muscle Stem Cell Function in Aging

In our bodies, the repair of damaged muscle is facilitated by a specialized population of cells known as muscle stem cells (MuSCs). These cells, which reside in muscle tissue, are crucial for maintaining muscle health and functionality. You can think of MuSCs as transformers, capable of transforming into different types of muscle cells with varied functions, depending on the body's needs [4].

In adults, MuSCs exist in a quiescent, or inactive, state and require external stimuli or signals to become active. This quiescent state is crucial for preserving the stem cells' regenerative potential over the long term, preventing premature depletion. When muscle damage occurs, external cues in the form of cytokines (signaling molecules) and growth factors activate MuSCs. These signals are typically released by injured muscle fibers and inflammatory cells that migrate to the site of injury [4].

Upon activation, MuSCs undergo a process of cell division, producing two distinct pools of cells. The first pool consists of fusion-competent muscle progenitor cells, which are committed to repairing and regenerating the damaged muscle tissue. These progenitor cells fuse with existing muscle fibers or form new muscle fibers, thereby restoring muscle function. The second pool comprises uncommitted stem cells that remain in the quiescent state, serving as a reservoir for future muscle repair needs. This dual pathway ensures that there is a balance between immediate muscle repair and the preservation of a stem cell pool for ongoing muscle maintenance and future repair processes [4].

As we age, the muscle repair capabilities of muscle stem cells (MuSCs) diminish significantly. This decline in regenerative potential is partly due to alterations in the biological environment, or niche, surrounding these cells. The niche comprises various proteins, signaling molecules, and other extracellular matrix components that provide essential support and regulatory cues to MuSCs.

With aging, the composition and abundance of these proteins and substances change, negatively impacting MuSC function. For instance, there is often an increase in inflammatory cytokines and a decrease in growth factors that are crucial for MuSC activation and muscle repair. This shift in the local environment can lead to a less supportive niche, reducing the effectiveness of MuSCs in responding to muscle damage.

Moreover, aged MuSCs themselves exhibit intrinsic changes, including reduced proliferative capacity and increased susceptibility to cellular stress. These intrinsic alterations, combined with an altered niche, contribute to a decline in the overall efficiency of muscle repair. This phenomenon is a key factor in sarcopenia [4].

The Impact of Young Blood on Muscle Stem Cell Function and Regeneration

This phenomenon is highlighted in a pivotal study titled "Rejuvenation of Aged Progenitor Cells by Exposure to a Young Systemic Environment," conducted by Dr. Irina Conboy and Dr. Michael Conboy from UC Berkeley's Department of Engineering. Published in the prestigious science journal Nature, this research involved a procedure known as parabiosis, where two mice are surgically joined to share their circulatory systems. The study revealed that older mice paired with younger ones exhibited enhanced muscle repair compared to those paired with similarly aged mice. This improved repair capability is attributed to the younger blood environment, which is rich in factors that boost the growth and healing abilities of muscle stem cells (MuSCs) in older mice. Factors present in young blood, such as growth factors and anti-inflammatory cytokines, appear to rejuvenate the aging MuSCs, enhancing their regenerative potential and muscle repair capacity. [10]

Conversely, research has also observed the opposite effect. When young muscle tissues were transplanted into older rats, these tissues demonstrated a decrease in muscle mass and strength. In addition to their impaired function, the angiogenesis of the grafted muscle was markedly compromised in the aged host [11]. Angiogenesis, the process of developing new blood vessels from pre-existing ones, is essential for the health of body tissues and organs. It facilitates the delivery of oxygen and nutrients and the removal of waste products [12]. However, in older hosts, this vital process was significantly hindered in the transplanted muscle tissue. With fewer blood vessels forming around the grafted muscle, its growth and maintenance were at risk, contributing to the observed decline in muscle mass and function.

These experimental studies, such as those with parabiotic mice, underscore the profound impact of the external environment on MuSCs. Young serum promotes regenerative responses, enhancing muscle repair and overall tissue health, while older serum leads to muscle degradation and impaired regeneration. This body of research suggests that the systemic environment, including circulating factors in the blood, plays a crucial role in the functionality and regenerative capacity of MuSCs.

One of the serum factors that has garnered significant interest in these studies is oxytocin, a hormone known for its roles in social bonding and reproduction. Emerging research out of the Conboy Laboratory indicates that oxytocin may be one of the serum factors that stimulated muscle tissue repair, potentially offering therapeutic benefits for conditions such as sarcopenia and Sarcopenic Obesity.

Understanding Oxytocin (OT)

Oxytocin (OT), a peptide hormone composed of nine amino acids, is synthesized in specific areas of the hypothalamus, a brain region instrumental in regulating feeding behavior, stress response, and social interactions. Once produced, oxytocin follows two distinct pathways for distribution, much like a boat navigating through different river channels to reach varied destinations. One pathway carries oxytocin to the bloodstream, circulating it throughout the body's periphery, below the brain. The other route directs it to various brain structures, including the amygdala, hypothalamus, hippocampus, and nucleus accumbens. These structures are integral components of the limbic system, which plays a key role in regulating mood, emotions, and overall well-being.

In different regions and situations, oxytocin manifests a variety of effects. For instance, in pregnant women, it is crucial for initiating labor by stimulating uterine contractions. Additionally, oxytocin is released during breastfeeding, fostering a vital bond between the mother and her infant. Beyond these roles, oxytocin is also linked to intimacy, sexual behavior, and social bonding, earning it the nickname "the love hormone." It enhances social interactions and emotional connections, playing a critical role in forming and maintaining interpersonal relationships.

So what does this have to do with sarcopenic obesity? Emerging research from the Conboy Laboratory suggests that oxytocin may act as a key serum factor that stimulates muscle tissue maintenance and repair. In the following sections, we will review this research and explore oxytocin's potential therapeutic benefits for conditions such as sarcopenia and sarcopenic obesity.

Oxytocin and Muscle Tissue Maintenance and Repair

Recent studies have highlighted a potentially crucial role of oxytocin in muscle strength and development. As individuals age, there tends to be a gradual decrease in the levels of oxytocin in the body. This decline is one of various factors that contribute to the weakening of muscle function, which can result in sarcopenia.

A pivotal study titled "Oxytocin is an Age-Specific Circulating Hormone that is Necessary for Muscle Maintenance and Regeneration" by Dr. Elabd, Dr. Cousin, and Irina Conboy from the UC Berkeley Department of Bioengineering was published in the highly prestigious journal Nature. This research investigated the effects of oxytocin administration on skeletal muscle tissue health in elderly mice. The study revealed that oxytocin treatment significantly improved the function of aging muscle stem cells (MuSCs), thereby aiding in muscle regeneration and enhancing overall muscle function [14].

Muscle stem cells (MuSCs) have special receptors that are designed to recognize and attach to oxytocin. When oxytocin binds to these receptors, it triggers a chain reaction inside the cell that ultimately leads to the stimulation of the muscle stem cells [14].

When oxytocin binds to these receptors, it initiates a series of reactions within the cell, starting with the activation of a protein called RAS. Once activated, RAS sets off a chain of biological events that lead to the activation of an important signaling pathway called the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase (MAPK/ERK) pathway. This pathway is vital for several cell functions, including cell growth, differentiation (the process by which cells change into other cell types), survival, and programmed cell death (apoptosis) [14].

In the context of muscle stem cell proliferation (which means the process by which these cells multiply and grow), this MAPK/ERK pathway acts like a relay system. It transmits signals that promote the division and growth of muscle stem cells, beginning with the initial binding of oxytocin to its receptors. A key part of this pathway involves a protein called MEK activating another protein called ERK. Once activated, ERK moves from the cell's cytoplasm (the jelly-like substance inside the cell) to the nucleus (the cell's control center). In the nucleus, ERK interacts with and activates proteins that regulate gene expression. These activated proteins then increase the expression of genes involved in cell growth and survival [14].

Therefore, in a nutshell, oxytocin helps stimulate muscle regeneration by encouraging the proliferation of muscle stem cells. It does this through its role in activating the MAPK/ERK pathway, leading to a cascade of events that support cell growth and division [14].

This discovery was further supported by additional research. The scientists investigated how decreasing oxytocin levels affect young skeletal muscle tissue. They employed specific drugs to block oxytocin from attaching to the receptors on Muscle Stem Cells (MuSCs). By doing this, they were able to reduce the activity of the MAPK/ERK signaling pathway. The consequence of this reduction was premature aging in the muscle tissue. In their experiments, mice began to show signs of sarcopenia, which is the loss of muscle mass and a decline in muscle regeneration ability, at just 12 months old. This is a relatively young age for such symptoms to appear in mice. These results further highlight the significant role that oxytocin plays in maintaining and repairing muscle tissue [14].

Having demonstrated that a lack of oxytocin (OT) resulted in diminished regeneration of aged muscle after injury, the researchers next sought to examine whether OT was involved in age-associated sarcopenia. To test this hypothesis, they assessed the mass of the gastrocnemius (GA) and tibialis anterior (TA) muscles of 12-month-old oxytocin knockout (KO) mice and their wild-type (WT) littermates. In this context, "knockout" refers to genetically engineered mice in which the gene responsible for producing oxytocin has been completely deactivated, while "wild-type" refers to mice that possess a normal, non-mutated version of the gene. The results showed that OT deficiency led to significantly smaller muscles: OT KO mice displayed a 32% decrease in muscle mass for the TA and a 22% decrease for the GA compared to their WT littermates [14].

These oxytocin studies shed light on the potential serum factors that contributed to healthy muscle tissue observed in the young blood during the parabiosis studies. Specifically, we have outlined how oxytocin stimulates the activation of muscle stem cells, leading to healthy muscle generation. However, is there an underlying mechanism in which it could target age-related fat accumulation?

Oxytocin and Fat Compostion

Apart from its role in muscle repair, recent studies have shed light on the potential of oxytocin in weight management, with findings supported by animal research. In one notable study, the health of male mice lacking oxytocin receptors was longitudinally evaluated. These mice displayed a higher propensity for obesity later in life, characterized by increased belly fat and higher fat levels in their blood after fasting periods. Interestingly, this occurred despite their daily food consumption and natural physical activity levels being similar to those of their counterparts with functional oxytocin receptors [15].

Another study focused on mice genetically modified to be more susceptible to obesity. In genetics, 'specific sequences' in genes are responsible for coding particular proteins. Altering these sequences—by removing, changing, or substituting elements—can impair the protein's functionality. In this study, researchers modified the sequence of the single-minded 1 (Sim1) gene, which encodes the SIM1 protein. This protein is crucial in preventing obesity by regulating weight gain and food intake. The modification reduced the functional capacity of the SIM1 protein, leading to an increased likelihood of obesity in these mice. Notably, these mice had significantly lower oxytocin levels compared to normal mice. This suggests a negative correlation between oxytocin levels and obesity, where lower oxytocin levels are linked to a greater tendency towards obesity. The study also explored the impact of oxytocin supplementation on these obese mice, finding that it reversed their excessive food intake and weight gain [16].

Overall, this study highlights oxytocin's emerging role not only in muscle repair but also in weight management. Mice without oxytocin receptors tended more towards obesity, even with comparable food intake and activity levels to normal mice. In those genetically predisposed to obesity, oxytocin supplementation proved effective in reversing excessive food intake and weight gain.

Oxytocin as a Therapeutic Agent for Sarcopenic Obesity in Older Adults

From the review above, it seems that oxytocin plays a role in muscle repair and weight management. Given these dual effects, new interest has been sparked in exploring the role of oxytocin as a treatment for Sarcopenic Obesity in older adults.

In a notable clinical trial involving 21 older adults (average age 67.5 years) who were both obese and had slow gait speeds (an indicator of sarcopenia), researchers examined the effects of oxytocin supplementation. The participants were randomly assigned to receive either intranasal oxytocin or a placebo (an inactive substance) over eight weeks, in a double-masked, placebo-controlled setting [17]. The trial demonstrated that oxytocin administration was well-tolerated, with no significant side effects. Notably, those who received oxytocin experienced an increase in muscle mass, averaging a 2.25 kg gain, compared to the placebo group. There was also a tendency towards a decrease in fat mass.

The study also investigated the impact of oxytocin (OT) on low-density lipoprotein (LDL) levels in the blood. LDL, often termed "bad cholesterol," is a type of lipoprotein composed of fats and proteins, responsible for transporting cholesterol from the liver to other cells in the body. Elevated levels of LDL cholesterol are linked to an increased risk of atherosclerosis, a condition where arteries become narrowed and hardened due to cholesterol and other substance buildup. This can lead to serious cardiovascular diseases like heart attacks and strokes. Therefore, monitoring LDL levels is crucial for cardiovascular health. Participants who received oxytocin showed lower LDL levels compared to those in the placebo group. [17]

Overall, by increasing muscle mass and decreasing fat mass and LDL levels, oxytocin demonstrated potential as a therapeutic agent in managing sarcopenic obesity (SO) in the elderly. This proof-of-concept study paves the way for further research into oxytocin as a possible treatment for the combined challenges of obesity and muscle loss in aging populations.

Conclusion

Despite efforts to implement lifestyle changes, aging often leads to challenges like a slower metabolic rate, weight gain, and muscle loss. This review delves into the potential of oxytocin, commonly referred to as the 'love hormone,' in addressing the complexities of sarcopenic obesity in older adults. Sarcopenic obesity is characterized by a simultaneous decline in muscle mass and an increase in body fat, presenting a significant health concern for this demographic. Aging affects how the body consumes, digests, and responds to dietary proteins. This results in altered protein turnover, reduced protein synthesis, and increased protein breakdown, leading to a net effect of decreased muscle mass and a rising propensity for sarcopenic obesity.

Additionally, Muscle Stem Cells (MuSCs) lose functional capacity with age, impairing the regenerative potential of older muscles. External factors influencing MuSCs, as revealed in studies using parabiotic mice, highlight the environmental impact on muscle health. Understanding these complex factors sheds light on the mechanisms underlying the co-occurrence of sarcopenia (muscle loss) and obesity in sarcopenic obesity.

Fortunately, oxytocin has emerged as a significant factor in muscle tissue maintenance and obesity management. Research indicates that administering oxytocin activates the MAPK/ERK pathway in MuSCs, enhancing their proliferation and regenerative potential.

Furthermore, experimental studies on obese mice have demonstrated oxytocin's potential in countering obesity by reversing excessive food intake and weight gain. Given the dual benefits of oxytocin in weight management and muscle repair, clinical trials are actively being performed to evaluate its effects on sarcopenic obesity. In a recent trial, participants receiving oxytocin experienced increased lean muscle mass, a trend towards decreased fat mass, and lower LDL levels. This study suggests that oxytocin could solve the challenges posed by sarcopenic obesity in aging individuals. The intricate interplay between oxytocin and sarcopenic obesity presents a promising avenue for enhancing health outcomes in aging populations.