Mapping human aging in the search for eternal youth
Key Takeaways
The science of anti-aging is rapidly advancing, with an eye toward early interventions to slow or prevent the development of age-related illness.
Recent research has focused on mapping regions of the brain and genes linked to aging, which involve memory, emotions, and more.
Translational efforts are targeting NLRP3 and other mediators of chronic inflammation, along with the promotion of apelin signaling, which may play a role in the development of neurodegenerative and other age-related disorders.
The quest to defy age is a timeless archetype. In Greek mythology, for example, Eos fell in love with Tithonus (son of the King of Troy), and asked Zeus to grant him eternal life. Eos forgot, however, to also request eternal youth. Thus, Tithonus lived long yet shriveled with age.[]
The myth of anti-aging could soon be reified, as enterprising researchers embark on mapping human aging with an eye toward intervention.
Mapping genome regions
The human brain is a complex and dynamic organ that undergoes structural changes throughout a person's lifetime. These changes can be influenced by a variety of factors, including genetics, environment, and lifestyle.
This process of structural modification of the brain over time was described in an article in Nature Neuroscience.[] During early development, the brain undergoes rapid growth and development, with the formation of new neural connections and the pruning of unused or unnecessary connections. This process continues through adolescence and early adulthood, with the brain reaching its peak in terms of size and complexity in the mid-20s.
As a person ages, the brain undergoes a process of natural atrophy, with a gradual loss of neurons and connections. This can lead to changes in cognitive function, including memory decline and slower processing speed.
Alterations in brain growth or increased cognitive decline likely play a role in various neurodegenerative, psychiatric, and developmental conditions.
The Nature Neuroscience article reported on a study funded by the National Institute on Aging (NIA) and conducted by an international team of more than 200 scientists representing the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium. This genome-wide association study identified regions of the human genome that regulate the speed of brain aging, as announced in the study’s press release.[]
The researchers identified 15,640 participants worldwide who had received longitudinal MRIs.
They used the scans to assess baseline measures of the rate of growth or atrophy in areas of the brain necessary for memory, thinking, and emotions over time. The investigators then cross-referenced changes in brain tissue with about 1 million genetic biomarkers.
The meta-analysis of alterations in brain morphology spanning human life focused on changes in 15 brain structures and pinpointed the genes GPR139, DACH1, and APOE as correlated with metabolic processes. There was a global genetic overlap of factors, including cognitive function, schizophrenia, depression, insomnia, height, BMI, and smoking.
Gene definitions
GPR139: G protein-coupled receptor 139 (GPR139) is a gene that codes for a protein that is found in specific regions of the brain, including the thalamus, hypothalamus, and amygdala. Recent research has suggested that GPR139 may play a role in modulating anxiety, depression, and addiction. Specifically, GPR139 has been shown to interact with the neuropeptide Y (NPY) system, which is involved in the regulation of mood and stress responses.
DACH1: Dachshund family transcription factor 1 (DACH1) is a gene that codes for a protein that is involved in regulating the development and differentiation of neurons in the brain. Recent research has suggested that DACH1 may play a role in the formation of neural circuits.
APOE: Apolipoprotein E (APOE) is a gene that codes for a protein that is involved in the transport of lipids in the body. Research has shown that APOE is also expressed in the brain, where it plays a role in neuronal repair and maintenance. Certain variants of the APOE gene have been linked to an increased risk of developing Alzheimer's disease.
Connecting the dots: Genes and aging
The APOE ε4 allele (of Alzheimer’s and related dementia notoriety) was linked to accelerated tissue decline at the level of the hippocampus and amygdala. Additionally, abnormal buildup of the tau protein, which is also common in Alzheimer’s disease pathology, was found to be related to Down syndrome and amyotrophic lateral sclerosis. “The scientists see this as evidence of the connection of these genes to neurodegeneration and aging,” the NIA’s press release noted.
“In conclusion,” the Nature Neuroscience authors wrote, “our study shows that our genetic architecture is associated with the dynamics of human brain structure throughout life.” Although the present results may not be sufficient to explain brain changes in health and disease, the authors believe their findings “may direct future studies into brain development and ageing, and prevention and treatment of brain disorders.”
"Neurodegenerative disorders might be better understood when we identify genetic variants that influence brain atrophy over time, compared with identification of static genetic differences."
— Authors, Nature Neuroscience
Translational research
BioAge Labs, Inc., is a clinical-stage biotechnology company actively developing agents targeting the molecular causes of aging with the goal of extending life spans in healthy people. One intriguing lead is the inhibition of NLRP3 (NOD-like receptor family pyrin domain-containing protein 3) and other mediators of chronic inflammation. Such inhibitors could help prevent various age-related disorders. Data from their NLRP3 inhibitor program have been presented at major conferences, as mentioned in a press release.[]
NLRP3 is a key component of the inflammasome, a multi-protein complex that regulates the activation of pro-inflammatory cytokines in response to cellular stress, infection, or tissue damage. Dysregulation of the inflammasome and increased activation of NLRP3 has been implicated in the pathogenesis of a variety of chronic inflammatory disorders, including neurodegenerative diseases.[]
Preclinical studies have shown that NLRP3 inhibition may have a beneficial effect on cognitive decline. For example, a study in mice showed that NLRP3 inhibition with a small-molecule inhibitor improved cognitive function and reduced neuro-inflammation in a mouse model of Alzheimer's disease.[] Another study demonstrated that NLRP3 inhibition with a different small-molecule inhibitor improved cognitive function and reduced neuro-inflammation in a mouse model of traumatic brain injury.[]
In describing the significance of the BioAge research into NLRP3, the press release explained that the proprietary BioAge target-discovery platform elucidated NLRP3 activity as linked to cognitive decline and death.
Inhibiting NLRP3, as well as other contributors to chronic inflammation that were identified by the platform, could prevent various age-related disorders mediated by inflammation.
BioAge co-founder Kristen Fortney, PhD, said, in speaking to the press, “Our family of potent, structurally differentiated NLRP3 inhibitors demonstrates BioAge’s capability to discover novel compounds for promising targets emerging from our discovery platform. I am excited about the potential of these drugs to treat diseases driven by brain aging, and our team is looking forward to the opportunity to share recent data from this program at multiple important scientific gatherings.”
Apelin-pathway activity
In other research, BioAge mined their proprietary human biobanks to demonstrate that apelin-pathway activity is correlated with longevity, cognitive function, and mobility. The apelin pathway is a signaling pathway that involves the binding of the apelin peptide to its receptor, apelin receptor (APJ). This pathway has been implicated in a wide range of physiological processes, including cardiovascular function, glucose homeostasis, and inflammation. Skeletal muscle secretes apelin in response to exercise. This natural ligand of APJ moderates various facets of muscle growth, metabolism, and repair.
The apelin pathway has been shown to have anti-inflammatory effects in the brain. For example, it has been demonstrated that apelin can reduce neuro-inflammation and improve cognitive function in animal models of Alzheimer's disease and traumatic brain injury.[] Activity of this pathway declines with age.
BGE-105 is a highly selective, potent small-molecule agonist being developed by BioAge.[] BGE-105 binds APJ and triggers apelin signaling. In encouraging phase 1b results, this oral agent prevented muscle atrophy vs placebo in healthy participants aged 65 or older, following 10 days of strict bed rest. In April 2021, BioAge paired with Amgen Inc. to develop and market this agent.
What this means for you
Although it could be years before we see anti-aging agents commercially available, current research in the field is promising. Medical researchers are in the process of translating molecular findings to possible interventions to combat aging. In the meantime, physicians should continue to encourage their patients to live healthy lifestyles and exercise to ward off the burden of age-related disease.