Olduvai domains: humanity’s lucky brake

Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity

ABSTRACT Mitochondria are vital not only for energy production but also for regulating signaling pathways that influence aging. While mitochondrial dysfunction contributes to age‐related decline, emerging evidence shows that mild, regulated mitochondrial stress can paradoxically promote longevity. This review highlights recent advances in mitochondrial biology and aging across species. We explore the dual role of reactive oxygen species (ROS) as both damaging agents and signaling molecules that activate adaptive stress responses. Key pathways such as the mitochondrial unfolded protein response (UPR MT ) and integrated stress response (ISR) are discussed, including their tissue‐specific as well as non‐cell‐autonomous effects on aging. Additionally, we examine the impact of mitochondrial protein import/export, dynamics (fission, fusion, mitophagy, biogenesis), and quality control in aging. Finally, we address challenges in understanding context‐dependent mitochondrial responses and mitonuclear communication. Together, these insights position mitochondria as central regulators of aging and highlight their potential as therapeutic targets to enhance health span and longevity.

Does adolescence really last until age 32?

Those “turning points” in brain aging aren’t quite what you think

Towards Eldering

by Cash Ahenakew Part of the work of the GTDF collective has been around “growing up”. The term is used with reference to sobering up, to owning up and to showing up differently in the world. Previ…

A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates

Nested Hox expression domains are found in jawed vertebrates and in non-vertebrate chordates, but it is unclear whether there is a link between brain regionalization and Hox expression in jawless vertebrates; here, Hox expression is shown to be integrated with hindbrain segmentation in lampreys.

Single-cell multiregion dissection of Alzheimer’s disease

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1–3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology.

Mushrooms evolved psychedelics twice, baffling scientists

Researchers found that magic mushrooms and fiber caps independently evolved different biochemical pathways to create psilocybin. This convergence shows nature’s ingenuity, but the reason why remains unknown—possibly predator deterrence. Beyond evolutionary mystery, the discovery provides new enzyme tools for biotech, with promising applications for producing psilocybin-based medicines.

Invisible Designers: Brain Evolution Through the Lens of Parasite Manipulation

AbstractThe ability of parasites to manipulate host behavior to their advantage has been studied extensively, but the impact of parasite manipulation on the evolution of neural and endocrine mechanisms has remained virtually unexplored. If selection for countermeasures has shaped the evolution of nervous systems, many aspects of neural functioning are likely to remain poorly understood until parasites—the brain’s invisible designers—are included in the picture. This article offers the first systematic discussion of brain evolution in light of parasite manipulation. After reviewing the strategies and mechanisms employed by parasites, the paper presents a taxonomy of host countermeasures with four main categories, namely: restrict access to the brain; increase the costs of manipulation; increase the complexity of signals; and increase robustness. For each category, possible examples of countermeasures are explored, and the likely evolutionary responses by parasites are considered. The article then discusses the metabolic, computational, and ecological constraints that limit the evolution of countermeasures. The final sections offer suggestions for future research and consider some implications for basic neuroscience and psychopharmacology. The paper aims to present a novel perspective on brain evolution, chart a provisional way forward, and stimulate research across the relevant disciplines.

Amaranth Foundation - Longevity and Neuroscience

Amaranth Foundation funds groundbreaking work in longevity and neuroscience. Learn more about our grants, projects, and team .

Technological Approach to Mind Everywhere: An Experimentally-Grounded Framework for Understanding Diverse Bodies and Minds

Synthetic biology and bioengineering provide the opportunity to create novel embodied cognitive systems (otherwise known as minds) in a very wide variety of chimeric architectures combining evolved and designed material and software. These advances are disrupting familiar concepts in the philosophy of mind, and require new ways of thinking about and comparing truly diverse intelligences, whose composition and origin are not like any of the available natural model species. In this Perspective, I introduce TAME-Technological Approach to Mind Everywhere-a framework for understanding and manipulating cognition in unconventional substrates. TAME formalizes a non-binary (continuous), empirically-based approach to strongly embodied agency. TAME provides a natural way to think about animal sentience as an instance of collective intelligence of cell groups, arising from dynamics that manifest in similar ways in numerous other substrates. When applied to regenerating/developmental systems, TAME suggests a perspective on morphogenesis as an example of basal cognition. The deep symmetry between problem-solving in anatomical, physiological, transcriptional, and 3D (traditional behavioral) spaces drives specific hypotheses by which cognitive capacities can increase during evolution. An important medium exploited by evolution for joining active subunits into greater agents is developmental bioelectricity, implemented by pre-neural use of ion channels and gap junctions to scale up cell-level feedback loops into anatomical homeostasis. This architecture of multi-scale competency of biological systems has important implications for plasticity of bodies and minds, greatly potentiating evolvability. Considering classical and recent data from the perspectives of computational science, evolutionary biology, and basal cognition, reveals a rich research program with many implications for cognitive science, evolutionary biology, regenerative medicine, and artificial intelligence.

Differences in Krox20-Dependent Regulation of Hoxa2 and Hoxb2 during Hindbrain Development

During hindbrain development, segmental regulation of the paralogous Hoxa2 and Hoxb2 genes in rhombomeres (r) 3 and 5 involves Krox20-dependent enhancers that have been conserved during the duplication of the vertebrate Hox clusters from a common ancestor. Examining these evolutionarily related control regions could provide important insight into the degree to which the basic Krox20-dependent mechanisms, cis-regulatory components, and their organization have been conserved. Toward this goal we have performed a detailed functional analysis of a mouse Hoxa2 enhancer capable of directing reporter expression in r3 and r5. The combined activities of five separate cis-regions, in addition to the conserved Krox20 binding sites, are involved in mediating enhancer function. A CTTT (BoxA) motif adjacent to the Krox20 binding sites is important for r3/r5 activity. The BoxA motif is similar to one (Box1) found in the Hoxb2 enhancer and indicates that the close proximity of these Box motifs to Krox20 sites is a common feature of Krox20 targets in vivo. Two other rhombomeric elements (RE1 and RE3) are essential for r3/r5 activity and share common TCT motifs, indicating that they interact with a similar cofactor(s). TCT motifs are also found in the Hoxb2 enhancer, suggesting that they may be another common feature of Krox20-dependent control regions. The two remaining Hoxa2 cis-elements, RE2 and RE4, are not conserved in the Hoxb2 enhancer and define differences in some of components that can contribute to the Krox20-dependent activities of these enhancers. Furthermore, analysis of regulatory activities of these enhancers in a Krox20 mutant background has uncovered differences in their degree of dependence upon Krox20 for segmental expression. Together, this work has revealed a surprising degree of complexity in the number of cis-elements and regulatory components that contribute to segmental expression mediated by Krox20 and sheds light on the diversity and evolution of Krox20 target sites and Hox regulatory elements in vertebrates.

Jon Barron on Twitter / X

This idea that intelligence is solely a function of what you've observed since birth and not also a function of the 500 million years of evolution that preceded your birth is surprisingly sticky despite being demonstrably untrue. https://t.co/m2z5cN8Byb— Jon Barron (@jon_barron) January 28, 2026

Segmental expression of Hoxb-1 is controlled by a highly conserved autoregulatory loop dependent upon exd/pbx

Comparison of Hoxb-1 regulatory regions from different vertebrates identified three related sequence motifs critical for rhombomere 4 (r4) expression in the hindbrain. Functional analysis in transgenic mice and Drosophila embryos demonstrated that the conserved elements are involved in a positive autoregulatory loop dependent on labial (lab) family members. Binding of Hoxb-1 to these elements in vitro requires cofactors, and the motifs closely resemble the consensus binding site for pbxi, a homolog of the Drosophila extradenticle (exd) homeodomain protein.

Evolution as fitness landscape navigation: Concepts, Measures, and...

Fitness landscapes are mappings between genotypes, phenotypes, and fitness that shape evolution. In recent years, empirical work and theoretical models have greatly advanced our understanding of...

A running list of ATproto ideas - Tynan's Leaflets

Updated when the brain has more

Adam Tooze · Trouble Transitioning: What energy transition?

An honest account of energy history would conclude not that energy transitions were a regular feature of the past, but...