LongeCityNews Last Updated: 16 April 2026 - 06:19 PM

In Aging Cell, researchers have described how suppressing the ghrelin receptor improves muscle function and fights sarcopenia in older mice.

An appetite hormone with negative effects

Ghrelin has been well-documented as stimulating both appetite and growth [1]. However, this hormone, which increases with aging [2], has negative effects in older organisms; deleting ghrelin has been found to restore mitochondrial function, fight obesity, and restore muscle strength in older mice [3], thus delaying the age-related loss of muscle known as sarcopenia.

Removing ghrelin itself, however, may be difficult to translate to the clinic. These researchers, therefore, have chosen to target its receptor instead, noting that targeting its only known receptor “represents a viable anti-sarcopenia strategy” and “may be a more translatable approach than deleting the ghrelin ligand itself.” Therefore, this paper focuses on what happens when GHSR-1a is inhibited through various means in mice.

Less fatigue and more efficient mitochondria

For their first experiment, the researchers created a strain of mice that do not expres GHSR-1a and tested them at 6, 24, and 28 months of age. At 6 months, the mice with GHSR-1a knocked out were smaller than the other mice, in both total weight and lean body mass. However, the GHSR-1a knockout mice were stronger for their weight, and they were strictly stronger at 24 months of age. At 24 months of age, the knockout mice could run nearly 30% longer than wild-type mice, and at 28 months, this number increased to nearly 45%. Overall, metrics of sarcopenia were reduced in the knockout mice with aging.

There were also changes to fiber types, although there were no effects on fiber size. In wild-type mice, the number of IIB muscle fibers gradually declines. In the knockout mice, there was an increase in IIB fibers between 6 and 24 months, although there was a steep decrease between 24 and 28 months.

A direct muscle fatigue test, in which muscles are electrically stimulated in living mice, found that the knockout mice had less fatigue. 6-month-old knockout mice were able to exert more force than wild-type mice of the same age after two minutes or more of stimulation; 28-month-old knockout mice showed advantages over their wild-type counterparts at 30 and 60 seconds.

As expected, these physiological advantages were accompanied by mitochondrial benefits. The knockout mice did not exhibit a significant age-related decrease in citrase synthase the way wild-type mice did, nor did they have significant decreases in mitochondrial DNA (mtDNA) production. PGC-1α, which signals the formation of new mitochondria, increased at 28 months in the knockout mice instead of decreasing, and at that age, the knockout mice also benefited from higher levels of mitophagy, a process that clears out damaged mitochondria.

Reduces sarcopenia but does not improve lifespan

A gene expression analysis confirmed this knockout’s effects against sarcopenia, as the wild-type animals expressed genes in more ways that were associated with this disease. Many of these genes were directly related to mitochondrial respiration, and others were closely connected to muscular performance.

Unfortunately, there were no direct benefits for lifespan; the knockout mice and the wild-type mice lived for approximately the same amount of time.

The researchers then sought to see if these effects could be pharmacologically replicated. They tested PF-5190457, an inhibitor of GHSR-1a, for a month in 9- to 11-month-old mice. As expected, the appetite reduction caused by this inhibition reduced the treated mice’s body weight and fat mass. They also had increases in running time and mitophagy. Similar results were found in 25- to 27-month-old mice.

Targeting the ghrelin receptor is obviously not a cure-all for sarcopenia, as these effects were significant but not perfect. Furthermore, these researchers did not observe the lifespan increases that occurred in mice that had ghrelin targeted more directly [4]. However, this study makes it clear that it may be possible to, counterintuitively, reduce frailty in older organisms by suppressing instead of bolstering a growth hormone receptor.

Literature

[1] Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., & Kangawa, K. (1999). Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 402(6762), 656-660.

[2] Sun, Y., Garcia, J. M., & Smith, R. G. (2007). Ghrelin and growth hormone secretagogue receptor expression in mice during aging. Endocrinology, 148(3), 1323-1329.

[3] Guillory, B., Chen, J. A., Patel, S., Luo, J., Splenser, A., Mody, A., … & Garcia, J. M. (2017). Deletion of ghrelin prevents aging‐associated obesity and muscle dysfunction without affecting longevity. Aging Cell, 16(4), 859-869.

[4] Aguiar-Oliveira, M. H., & Bartke, A. (2019). Growth hormone deficiency: health and longevity. Endocrine reviews, 40(2), 575-601.

IGF-1 signaling is perhaps the most well studied mechanism of aging, with extensive work predating the modern enthusiasm for treating aging as a medical condition. Investigation of IGF-1 signaling in the context of aging was a fellow traveler to investigations of calorie restriction in the context of aging, and while these are roads that lead to a greater understanding of the evolution of aging and how pace of aging adapts to environmental circumstances, and have given rise to classes of drugs that may modestly slow aging, they are not likely to lead to any meaningful class of rejuvenation therapy. From a purely scientific point of view, the incomplete state of understanding of cellular biochemistry means that there is a lot left to learn on the topic of how aging progresses and shifts in response to circumstances, and how different systems and mechanisms interact with one another. Surprises remain to be discovered, though once again it seems unlikely that any of the surprises relating to IGF-1 signaling will be capable of giving rise to meaningful rejuvenation therapies.

One strategy to elucidate the relationships between the hallmarks of aging is to investigate how the disruption of one hallmark affects the trajectory of another. In doing so, it may be possible to assess whether these processes act independently, synergistically, or in opposition of each other as they shape human life span. In addition, this strategy may reveal if a hierarchy exists between aging pathways, which could lead to a more integrated and causally ordered model of the aging process. In this study, we apply this strategy to investigate the relationship between two critical drivers of the aging process, mitochondrial mutagenesis and insulin-like growth factor-1 (IGF-1) signaling.

A large body of evidence supports the idea that instability of the mitochondrial genome (i.e., changes in nucleotide sequence, copy number, and organization due to replication errors and DNA damage) leads to a progressive decline in mitochondrial function, which accelerates the natural aging process and contributes to a wide variety of age-related diseases, including sarcopenia, neurodegeneration, and heart failure. A similar body of work describes the role of IGF-1 signaling in the aging process. IGF-1 regulates the growth and metabolism of human tissues, and reduced IGF-1 signaling can not only extend mammalian life span but also confer resistance against various age-related diseases, including neurodegeneration, metabolic decline, and cardiovascular disease. However, how mitochondrial mutagenesis and IGF-1 signaling interact with each other to shape mammalian life span remains unclear.

Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Link: https://doi.org/10.1126/sciadv.aea4279

It is a struggle to derive evidence for causation from human data. It is well established that physical fitness correlates with a lower risk of age-related disease and mortality in humans, and well established that greater physical fitness causes a lower risk of age-related disease and mortality in animal studies. But as a practical matter one can't run the sort of study that would be needed to obtain direct proof of causation in humans. So researchers turn to approaches such as Mendelian randomization, in which one adds an additional set of genetic correlations in order to try to infer at least some support for causation. There are indeed genetic correlations with a tendency to greater physical fitness, and those do correlate in turn with risk of age-related disease and mortality.

We investigated potentially causal associations between genetically predicted aerobic fitness and multiple health phenotypes using a two-stage phenome-wide Mendelian randomization (MR) study. We screened 712 health-related phenotypes as outcomes using publicly available European-ancestry genome-wide association study (GWAS) summary statistics from OpenGWAS (Discovery GWAS n > 5,000), prioritizing non-UK Biobank/non-FinnGen datasets for Discovery when available and selecting an independent GWAS for Validation.

We identified 108 Discovery associations, of which 34 remained valid and statistically significant after Validation. Higher genetically determined aerobic fitness was associated with lower lacunar stroke risk, lower arterial stiffness, higher heart rate variability, lower diastolic blood pressure, more favorable anthropometric measures, lower use of antidiabetic drugs, lower asthma risk, lower C-reactive protein, higher bone mineral density, favorable liver function biomarkers, favorable platelet-related traits, multiple blood-count-derived hematological cell indices and counts, as well as higher years of schooling. Adverse associations were confined to atrial fibrillation, valvular heart disease, and systolic blood pressure.

Genetically determined aerobic fitness is linked to a broad pattern of favorable cardiometabolic, inflammatory, musculoskeletal, respiratory, hepatic, and hematological phenotypes, alongside a narrow set of potential cardiovascular hazards.

Link: https://doi.org/10.1249/MSS.0000000000003975

The tau protein is involved in maintaining stability of microtubule structures in the axons that connect neurons. It isn't the only protein that undertakes this task, and loss of functional tau doesn't produce immediate issues. Tau is important in some functions of memory, however, and mice lacking tau exhibit a range of cognitive defects that grow with age. Tau is well studied not for these aspects of its function, but because it is one of the few proteins that can be altered in a way that allows it to form solid aggregates that are disruptive to cell function. Tau aggregation to form the structures known as neurofibrillary tangles is a feature of late stage Alzheimer's disease. The consensus view of this stage of the condition is that tau aggregation and chronic inflammation form a feedback loop that accelerates dysfunction into widespread cell death in the brain.

The progression of Alzheimer's disease provides the appearance of a spread of tau aggregation from region to region in the brain. Study of the brain is challenging, however, and while there is a consensus on this point - that altered forms of tau can seed more dysfunction in a prion-like way and spread from cell to cell via synapses - there are other potential explanations for the observed outcomes. For example tau aggregation could be universal in the brain, but some regions are more vulnerable to the aggregation processes than others, and therefore exhibit a greater burden of neurofibrillary tangles earlier in the progression of the condition. Today's open access paper is an example of the way in which researchers must strive to circumvent the inability to directly access a large number of living human brains at various stages of Alzheimer's disease. Instead, the researchers synthesize a number of indirect approaches - models, genetics, postmortem tissues, and imaging data - to produce supporting evidence for the consensus view of a synaptic spread of tau aggregation.

Tau seeds induce neurofibrillary tangle formation across brain regions via individual-specific connectivity

Tau protein promotes assembly and stabilization of microtubules. In normal aging and Alzheimer's disease (AD), tau can become hyperphosphorylated, which reduces its affinity for microtubules and drives its mislocalization from axons to the body of the neuron and dendrites. Aberrant tau accumulation in the form of neurofibrillary tangles (NFTs) is a strong pathological correlate of cognitive decline. Based on postmortem human brain studies, the spatiotemporal progression of NFTs begins in layers II and III of the entorhinal cortex (EC), extends to the hippocampus and temporal cortex, entering the limbic system before reaching broader neocortical regions, which subsequent tau positron emission tomography (PET) studies confirmed in vivo. When tau is confined to the medial temporal lobe, patients typically experience memory problems, but once tau enters the neocortex, broader cognitive impairment often emerges.

The mechanisms underlying tau spread are unclear, but may rely on a process, referred to as tau seeding, in which abnormal forms of tau protein induce misfolding and aggregation of normal tau proteins in a template-dependent manner. Prior studies using cell cultures, mouse models, and human neuroimaging have each explored certain facets of tau pathology progression. However, whether endogenous tau seeds are the entities that induce NFTs across the aging human brain via naturally occurring connectivity remains to be confirmed. An alternative hypothesis that accounts for the observed NFT distribution is a gradient in region vulnerability, which does not involve tau seeds spreading from early-affected regions.

To investigate this question, we measured tau seed bioactivity data in synaptosomes from postmortem inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) tissues of 128 individuals and combined this data with genotype and antemortem fMRI measurements from the same individuals. Via multimodal integration of these data, we provided supporting evidence that tau seeds from an early-affected brain region induce local NFTs as well as drive tau seeds and NFTs in a late-affected, far-removed region. Also, extending past tau-PET studies that demonstrated spatial correspondence between tau deposition and connectivity patterns, we further showed that individual-specific intrinsic connectivity modulates tau seed-NFT relationships. Our results thus support the hypothesis that tau seeds use synaptic connections to spread tau across connected regions in the human brain.