LongeCityNews Last Updated: 21 August 2025 - 02:27 AM

Antagonistic pleiotropy is a term used to describe a biological mechanism that is helpful in one context, harmful in another. As most often used, this means helpful when young, harmful when old. The concept of antagonistic pleiotropy sits at the heart of any serious discussion of the evolution of aging, as well as the relationships between known mechanisms of aging and hallmarks of aging. The dominant view of aging is that it is a side-effect of natural selection operating more strongly on the characteristics of young individuals than on the characteristics of old individuals, favoring the evolution of mechanisms that enhance early survival and reproductive success at the expense of later survival and reproductive success. Optimizing for initial success no matter the later consequences is a winning strategy for near all ecological niches.

Examples of specific mechanisms and circumstances that illustrate the reality of antagonistic pleiotropy have been established in a number of species. Researchers are very interested in finding examples in humans, however. Given vast genetic and epidemiological databases, researchers have searched for longevity-associated mutations that also affect reproductive success, for example. This is challenging, as longevity-associated mutations with even modest effect sizes and replication in multiple study populations are thin on the ground. There is some debate over whether any of the human data is in fact a good demonstration of antagonistic pleiotropy. Nonetheless, researchers continue to work on the problem, as illustrated by today's open access paper.

Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans

Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited. In this study, Mendelian randomization (MR) was applied to investigate the associations between the ages of menarche or first childbirth and age-related outcomes and diseases. Ingenuity Pathway Analysis was employed to explore gene-related aspects associated with significant single-nucleotide polymorphisms (SNPs) detected in MR analysis. The associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes were validated in the UK Biobank by conducting regression analysis of nearly 200,000 subjects.

Using MR, we demonstrated that later ages of menarche or first childbirth were genetically associated with longer parental lifespan, decreased frailty index, slower epigenetic aging, later menopause, and reduced facial aging. Moreover, later menarche or first childbirth was also genetically associated with a lower risk of several age-related diseases, including late-onset Alzheimer's disease, type 2 diabetes, heart disease, essential hypertension, and chronic obstructive pulmonary disease. We identified 158 significant SNPs that influenced age-related outcomes, some of which were involved in known longevity pathways, including insulin-like growth factor 1, growth hormone, AMP-activated protein kinase, and mTOR signaling. Our study also identified higher body mass index as a mediating factor in causing the increased risk of certain diseases, such as type 2 diabetes and heart failure, in women with early menarche or early pregnancy.

We validated the associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes in the UK Biobank by conducting regression analysis of nearly 200,000 subjects. Our results demonstrated that menarche before the age of 11 and childbirth before 21 significantly accelerated the risk of several diseases and almost doubled the risk for diabetes, heart failure, and quadrupled the risk of obesity, supporting the antagonistic pleiotropy theory.

In a recent study, researchers identified the critical role that lithium plays in brain health and the development of mild cognitive impairment and Alzheimer’s disease. Supplementing with a lithium salt called lithium orotate can reverse many of its cognitive decline-related changes on the molecular and cellular levels [1].

The road less traveled

Understanding the underlying causes and factors related to Alzheimer’s disease is essential to developing effective therapies, which do not yet exist. The researchers of this paper focused on less explored factors such as metals, which play essential roles in the brain’s functioning and have not been deeply studied in the context of Alzheimer’s disease.

They started by assessing 27 metals in the brain and blood of aged people with different levels of cognitive abilities, including no cognitive impairment, mild cognitive impairment, and Alzheimer’s disease. They specifically focused on the prefrontal cortex, which is usually affected in Alzheimer’s disease, and used the cerebellum, the brain region that is not usually affected, for comparison.

Lithium and cognition

They identified that the levels of one metal, lithium, were significantly reduced in the prefrontal cortex of people with mild cognitive impairment and Alzheimer’s disease but not in the cerebellum. Lithium was also present in the amyloid beta (Aβ) plaques, and Alzheimer’s patients had higher concentrations of lithium in Aβ plaques compared to those with mild cognitive impairment.

In the next step, the researchers divided prefrontal cortex samples into two fractions: a plaque-enriched fraction and a fraction not containing amyloid plaques. Compared to people without cognitive impairment, there was less lithium in the prefrontal cortex non-plaque fraction of Alzheimer’s patients. They also noted a correlation between some cognitive abilities and lithium levels in the non-plaque cortical fraction.

Further data from older mouse models showed lower lithium levels in the non-plaque cortical fractions and lithium concentrations in the Aβ deposits, suggesting the isolation of lithium in the Aβ deposits that result in lower bioavailability.

Restricting lithium

Since previous experiments suggested decreased lithium bioavailability, the researchers imitated that state through restricting the lithium in the mouse diet by 92%, which led to a 89% drop in mean serum lithium and a 47–52% decrease in mean cortical lithium in the non-plaque fraction, suggesting the dietary approach was working in lowering lithium levels.

In mouse models prone to forming Aβ deposits, mice with reduced dietary lithium had increases in Aβ deposition and phospho-tau isoforms, Alzheimer’s disease-associated proteins, in the hippocampus compared to the age-matched, normally fed controls, which started to appear in relatively young mice and continued to accumulate with age.

A similar trend was observed in the wild-type mice; however, here the researchers observed an increase specifically in cortical and hippocampal Aβ42, the primary pathogenic Aβ form. Together, these results suggest that lithium deficiency accelerates Aβ deposits and phospho-tau accumulation.

A lithium-deficient diet also affected cognition in the mouse models prone to forming Aβ deposits and in the aging wild-type mice. It impaired learning, long-term memory, and novel-object recognition memory but didn’t impact spatial learning, locomotor activity, and exploratory behavior.

Lithium deficiency and Alzheimer’s similarities

Analysis of gene expression in the hippocampus, a part of the brain that is one of the first to be affected by mild cognitive impairment and Alzheimer’s disease, indicated many cell-type-specific changes in lithium-deficient mice that were prone to forming Aβ deposits.

Many of those changes overlapped with changes observed incortical biopsies obtained from people showing early-stage Aβ deposition, and even higher levels of overlap were observed when the researchers analyzed cortical biopsies from patients who were diagnosed with Alzheimer’s disease before or within one year of biopsy and who showed both Aβ and phospho-tau pathology.

Similarly, an analysis of microglia, the immune cells of the central nervous system, significantly overlapped the gene expression patterns of microglia in Alzheimer’s disease, including similarities to a reactive pro-inflammatory microglial state specific to Alzheimer’s disease and impaired Aβ clearance. This occured when either Alzheimer’s-prone mice or wild-type mice were deprived of lithium.

Lithium restriction also led to decreases in gene expression and proteins that relate to synaptic signaling and structure along with myelin, which forms a protective sheath around nerve fibers, in the aging mouse brain. This led to a loss of myelin itself, creating thinner myelin sheaths and a reduced number of certain types of cells in the nervous system.

The mediator of changes

The researchers analyzed differentially expressed genes to identify signaling pathways that lead to the outcomes of lithium deficiency. They identified a molecular target of lithium, serine-threonine kinase GSK3β, as a protein that regulated some of the affected signalling pathways and has a direct connection to Alzheimer’s disease, as tau is phosphorylated by GSK3β in Alzheimer’s disease. Activated GSK3β levels were increased in the hippocampal cells of lithium-deficient mice [2, 3].

When the researchers inhibited GSK3β in lithium-deficient animals or cell cultures, many of the lithium deficiency-related features were reversed, “including Aβ deposition, phospho-tau accumulation, myelination and microglial pro-inflammatory activation, as well as restoring the ability of microglia to clear Aβ.”

Reversing the decline

The researchers reasoned that since lithium is being sequestered by amyloid plaques, using lithium salts with reduced amyloid binding might have therapeutic potential. They identified lithium orotate as having the highest therapeutic potential and compared it with the clinical standard, lithium carbonate.

Compared to mice receiving lithium carbonate, the Alzheimer’s-prone mice that received low doses of lithium orotate had lower concentrations of lithium in Aβ plaques, more lithium in the non-plaque fraction, an almost complete absence of Aβ plaque deposition and phospho-tau accumulation, a reversed expression of lithium deficiency-related genes, a nearly complete reversal of memory loss, and improved learning and spatial memory.

The effect of low-dose lithium was further investigated with a focus on normal brain aging in wild-type mice. The researchers noted the positive impact of lithium orotate on brain age-related conditions, specifically, a reduction in pro-inflammatory cytokines, a restoration of the ability of microglia to degrade Aβ, synapse maintenance, and a reversal of learning and memory decline without any toxic effects.

A new and promising idea

“The idea that lithium deficiency could be a cause of Alzheimer’s disease is new and suggests a different therapeutic approach,” said senior author Bruce Yankner, professor of genetics and neurology in the Blavatnik Institute at HMS. “What impresses me the most about lithium is the widespread effect it has on the various manifestations of Alzheimer’s. I really have not seen anything quite like it all my years of working on this disease,” Yankner adds.

“One of the most galvanizing findings for us was that there were profound effects at this exquisitely low dose,” Yankner adds. This is especially important since higher doses of lithium could lead to kidney and thyroid toxicity in aged individuals. Still, such toxicity was not detected in mouse models treated with low lithium doses [4].

He also adds that lithium treatment is much different than current Alzheimer’s approaches: “My hope is that lithium will do something more fundamental than anti-amyloid or anti-tau therapies, not just lessening but reversing cognitive decline and improving patients’ lives,” he said.

However, Yankner also cautions and reminds people that human trials are imperative to ensure this approach is a viable treatment: “You have to be careful about extrapolating from mouse models, and you never know until you try it in a controlled human clinical trial,” Yankner said. “But, so far, the results are very encouraging.”

Literature

[1] Aron, L., Ngian, Z. K., Qiu, C., Choi, J., Liang, M., Drake, D. M., Hamplova, S. E., Lacey, E. K., Roche, P., Yuan, M., Hazaveh, S. S., Lee, E. A., Bennett, D. A., & Yankner, B. A. (2025). Lithium deficiency and the onset of Alzheimer’s disease. Nature, 10.1038/s41586-025-09335-x. Advance online publication.

[2] Folke, J., Pakkenberg, B., & Brudek, T. (2019). Impaired Wnt Signaling in the Prefrontal Cortex of Alzheimer’s Disease. Molecular neurobiology, 56(2), 873–891.

[3] Leroy, K., Yilmaz, Z., & Brion, J. P. (2007). Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathology and applied neurobiology, 33(1), 43–55.

[4] Kakhki, S., & Ahmadi-Soleimani, S. M. (2022). Experimental data on lithium salts: From neuroprotection to multi-organ complications. Life sciences, 306, 120811.

While all tissues age into dysfunction, the primary cause of human mortality is the aging of the cardiovascular system into heart failure, stroke, and heart attack, combined with the consequences of progressively worsening cardiovascular function in other organs. The way in which cardiovascular aging manifests is well documented, and the underlying processes of aging that contribute to the observed outcomes are also fairly well understood at the high level. The challenge lies in establishing exactly how the low-level mechanisms of aging give rise to changes and loss of function in the heart and vasculature. This is a task that may not even be needed, if instead the research community focused on ways to repair the molecular damage of aging. We don't need to fully understand how exactly any specific harm contributes to cardiovascular disease if we build a means to address it and observe benefits to result from the use of that therapy.

Aging is a slow, progressive, and inevitable process that affects multiple organs and tissues, including the cardiovascular system. The most frequent cardiac and vascular alterations that are observed in older adults (especially patients aged ≥80 years) are diastolic and systolic dysfunction, progressive stiffening of the vascular wall and endothelial impairment usually driven by an excess of extracellular matrix (ECM) and profibrotic substances, reduced levels of matrix metalloproteinases (MMPs), or by amyloid and calcium deposits in myocardium and valves (especially in aortic valves). Moreover, deformation of the heart structure and shape, or increased adipose tissue and muscle atrophy, or altered ion homeostasis, chronotropic disability, reduced heart rate, and impaired atrial sinus node (SN) activity are other common findings.

Interestingly, aging is often associated with oxidative stress, alterations in the mitochondrial structure and function, and a low-grade proinflammatory state, characterized by high concentrations of cytokines and inflammatory cells, without evidence of infectious pathogens, in a condition known as 'inflammaging'. Aging is a well-recognized independent risk factor for cardiovascular disease and easily leads to high mortality, morbidity, and reduced quality of life. Recently, several efforts have been made to mitigate and delay these alterations, aiming to maintain overall health and longevity. The primary purpose of this review was to provide an accurate description of the underlying mechanisms while also exploring new therapeutic proposals for oxidative stress and inflammaging. Moreover, combining serum biomarkers with appropriate imaging tests can be an effective strategy to stratify and direct the most suitable treatment.

Link: https://doi.org/10.31083/RCM27437

Persistent infection via HIV, herpesvirus, or a range of other pathogens capable of evading or subverting the immune system might reasonably be thought of as producing accelerated aging. The dysfunction produced by these infections usually centers around the immune system, but this in turn negatively affects the function of tissues and systems throughout the body. Aging is an accumulation of damage, and persistent infection produces forms of damage that overlap with those generated during the normal course of aging. Here, researchers discuss the range of mechanisms thought to be involved.

Many models of aging assume that processes such as cellular senescence or epigenetic alteration occur under sterile conditions. However, humans sustain infection with viral, bacterial, fungal, and parasite pathogens across the course of a lifetime, many of which are capable of long-term persistence in host tissue and nerves. These pathogens - especially members of the human virome like herpesviruses, as well as intracellular bacteria and parasites - express proteins and metabolites capable of interfering with host immune signaling, mitochondrial function, gene expression, and the epigenetic environment.

This paper reviews these and other key mechanisms by which infectious agents can accelerate features of human aging. This includes hijacking of host mitochondria to gain replication substrates, or the expression of proteins that distort the signaling of host longevity-regulating pathways. We further delineate mechanisms by which pathogen activity contributes to age-related disease development: for example, Alzheimer's amyloid-β plaque can act as an antimicrobial peptide that forms in response to infection.

Overall, because many pathogens dysregulate mTOR, AMPK, or related immunometabolic signaling, healthspan interventions such as low-dose rapamycin, metformin, glutathione, and NAD+ may exert part of their effect by controlling persistent infection. The lack of diagnostics capable of detecting tissue-resident pathogen activity remains a critical bottleneck. Emerging tools - such as ultrasensitive protein assays, cell-free RNA metagenomics, and immune repertoire profiling - may enable integration of pathogen detection into biological age tracking. Incorporating infection into aging models is essential to more accurately characterize drivers of senescence and to optimize therapeutic strategies that target both host and microbial contributors to aging.

Link: https://doi.org/10.1016/j.arr.2025.102865