Cancer-killing cells in those humans live to 110 or longer

Amazing stuff! Good news! Cancer is history (soon)!

"People who live to 110 years and older have large populations of a rare type of immune cell that can kill cancer.

These killer T cells might help people to live to extraordinarily long ages by fighting off cancer — although this has yet to be proved.

“Most of immune ageing research has focused on decline,” [what a mistake!] ... “Our study suggests that even at extreme old age, the immune system may still selectively adapt.”"

"The current study builds on a 2019 finding by Hashimoto and his colleagues that supercentenarians have relatively large numbers of rare CD4 cytotoxic T lymphocytes (CD4 CTLs).

Cytotoxic cells kill other cells. CD4 CTLs typically make up less than 5% of the total population of T cells in the body. They’re not as well studied as other kinds of T cell, but they are commonly detected during viral infections, and there’s increasing evidence that they can kill cancer cells, including lung cancer and melanoma cells. Hashimoto says that his team wanted to find out at what age CD4 CTLs proliferate.

Supercentenarians are challenging to study because not many people live that long, says Hashimoto. In Japan, where his team did the study, there are only about 150 people aged 110 or older, he says. The study enrolled 28 participants, including some relatively young people: eight individuals aged 70–90, ten centenarians (people 100–109 years old) and ten supercentenarians.

As the researchers had previously found, CD4 CTLs were abundant in supercentenarians. But they were also found in large numbers in people aged 100 and older, suggesting that this immune adaptation begins around that age. The younger people had normal abundance of these cells, with CD4 CTLs making up 4% of their total T cells. The proportion was around 10% in centenarians and around 18% in supercentenarians.

And they found that these cells seem to be responding to specific immune threats. ... In the study’s centenarians and supercentenarians, the researchers found that single clonal lines made up a large percentage of the total CD4 CTLs. In the sample of one centenarian, for example, 53.8% of the cells were identical to each other. This suggests that their immune systems were leaping into action in response to a particular persistent trigger. ...

To get some clues, they examined the receptors found on the most common CD4 killer cell lines. They compared the amino-acid sequences of these cell lines with those in a database of CD4 cell receptors. Around 30 sequences from the study matched those from people with cancer in the database. Matches to people with lung cancer were most frequent, even though none of the people in the study had experienced any kind of cancer during their lives. ..."

From the highlights and abstract:

"Highlights

• CD4 CTLs expand around age 100 without signs of exhaustion

• A CD27−CD28+ state marks the intermediate helper-to-killer transition

• Large private CD4 CTL clones suggest repeated antigen exposure

• Single clones diversify cytokine profiles after ex vivo stimulation

Summary

Our previous study identified CD4 cytotoxic T lymphocytes (CD4 CTLs) as a hallmark of supercentenarians.

CD4 CTLs have primarily been studied in disease contexts; however, their role in healthy aging remains unclear.

Using single-cell immune profiling, we analyzed T cells from supercentenarians and found that CD4 CTLs begin to expand around the age of 100, characterized by sequential CD27/CD28 loss without exhaustion.

CD4 CTLs were dominated by large clones, with top clones averaging 33.3%, indicating repeated stimulation by persistent antigens.

Furthermore, CDR3β sequences of the top clones matched those of T cells expanded in tumors, particularly lung cancer.

Ex vivo stimulation experiments revealed that CD4 CTLs consist of subgroups defined by interleukin expression patterns, suggesting their plasticity within the same clone.

These findings suggest that CD4 CTLs expand and diversify as an adaptation to persistent antigens, potentially contributing to longevity through cancer suppression."

Nature Briefing: Cancer

How do people live beyond 110? Abundance of cancer-killing cells might be key "Research on people 110 years and older reveals an immune system that continues to adapt."

CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging (open access)

Misao Okawa celebrated her 117th birthday in 2015. Is she still alive?

Graphical abstract

Figure 1 Overview of single-cell immune profiling

Figure 6 Characteristics of activated CD4 CTLs

Why Aging May Be a Program, Not a Breakdown

Very recommendable! An interesting hypothesis! Will we one day find the triggers of the aging program in humans?

"...  Yet the underlying biology of aging remains a matter of uncertainty and debate.

Many lines of research align with the theory that aging is a direct result of decay — the inevitable degradation of molecules (including proteins or DNA), organelles, cells, or whole organs — from external assault or inexorable breakdown. When the body’s repair mechanisms fail to keep pace with these changes ...

Far from a random but linear process of wear and tear ... aging is a stepwise, programmed, orderly affair. “The destruction of the system is programmed at a very early stage,” ... Using technology that offers a systemwide view of the aging process in mice ... has outlined discrete stages of aging, akin to those of embryonic development, that are defined by changes in molecular signals and specific cell populations. In humans, the process likely begins before age 30. ...

In one series of experiments ... processed 21 million cells, sampled from 14 tissues or organs in about 50 male and female mice at five life stages, and built a data set of gene expression for each cell. “It’s extremely large-scale data,” ... “You know which organ it’s from and which age it’s from, and you also know extensive molecular information.” Each stage was marked by a dramatic decline in or expansion of specific cell types. ...

Two of his landmark papers, published in 2025 and 2026 in Science, point to a radical redistribution of the cells that make up the body as mammals age, and describe some of the epigenomic instructions that guide this process. “There are molecular changes and maybe some other changes in aging,” ... “but they all converge in the remodeling of the cell society.” ...

In one set of studies, we extracted more than 20 million cells from various organs from mice of different ages: 3, 6, 12, 16, and 23 months — roughly equivalent to 20, 30, 50, 60, and 75 years in humans. We analyzed the expression of 20,000 genes per cell and used this information to define the cell types. Then we tracked their population dynamics. ...

We found that not every cell type gets changed in aging. We identified 536 main cell types and 1,828 subtypes. Only about one-quarter of these subtypes show a strong shift in aging. Others remain stable across the lifespan.

It is surprising to find that changes in aging are not universal across all the cells, that there are specific cell populations that are more vulnerable. ...

We found that aging can be separated into distinct time windows. In each window, specific groups of cells show coordinated dynamics.

In the early phase, for example, we see that some cell types are rapidly depleted. This is followed by another phase, in which other cells are greatly expanded. ...

researchers have observed a phenomenon called “abrupt aging” in middle-aged humans that is consistent with the cell population dynamics we saw. When researchers analyze protein signatures in human blood, they see a significant change between the mid-40s and late 50s. People also tend to report an abrupt decline in function in middle age ...

What do your findings tell us about the nature of aging?

Previously, people saw aging as a linear accumulation of damage to molecules such as proteins and DNA.

But we found that aging is not a linear process. It’s more like a developmental process, in which there are distinct stages that involve coordinated changes in specific cell types across different organs. Our claim is that aging is not so much molecular damage as a remodeling of the entire cell society. ...

Our technology allows us to examine the genomic program that governs the function of each cell — which regions of the genome are active and which are silent. If it’s random molecular damage, we might see random changes across the genome. But we always see the same regions that are open [active] or closed [silent] at each stage. We identified 280,000 genomic regions that are reproducibly open or closed during the aging process in specific cell types. ...

So the body has a program for aging?

Yes, the abrupt changes in mammalian aging along with the coordinated cellular dynamics at each stage suggest there are upstream signals that control aging. It’s like a tree in autumn: Its leaves fall not in a linear way but in just two weeks during the transition between summer and autumn. ..."

From the editor's summary and abstract (1):

"Editor’s summary

Aging is a complex process that results in functional changes across tissues and cell types. These changes are beginning to be documented across organismal lifespans using single-nuclei RNA sequencing. Zhang et al. generated cell atlases across multiple time points in both a commonly used mouse strain and two immunodeficient strains and their wild-type counterparts, cataloging changes in cell populations and expression changes within cell types over these time points. Investigating the role of a diminished immune complement, the authors found that certain intestinal epithelial populations increased in the absence of these adult lymphocytes. This study provides a resource for researchers studying aging, particularly in the context of immunodeficiency. ...

Structured Abstract

INTRODUCTION

As we age, certain cell types within the diverse cellular landscape of various organs undergo substantial changes. These alterations not only affect the overall function of the organism but also play a critical role in the development of age-related diseases.

Cataloging these vulnerable cell types is essential for understanding the cellular basis of aging-related pathologies and for identifying potential interventions. However, the inherent heterogeneity and varying cell proportions within each organ make it challenging to identify rare but crucial aging-associated cell types. Although single-cell genomics studies have examined the effect of aging on various organs, conventional studies face challenges such as imbalanced sex representation, biased age sampling, and limited cell coverage. These limitations hinder a comprehensive and systematic dissection of the aging process at the cellular level.

RATIONALE

To establish a panoramic cellular characterization of organismal aging in mammals and identify cell types associated with the aging process, we optimized the low-cost, high-throughput EasySci method to establish a unified single-nuclei profiling platform for all major mammalian organs. We collected and profiled tissue and organ samples from mice across their life span using a sex-balanced cohort with multiple replicates, all processed by a single individual to minimize batch effects.

To dissect intercellular regulatory networks, we used a cell-knockdown strategy to selectively deplete mature lymphocytes in vivo in adult and aged mice, allowing us to investigate their role in regulating the population dynamics of other cell types during aging.

RESULTS

We generated PanSci, an atlas comprising single-nucleus transcriptome profiles of 21,786,931 cells from >600 samples, covering 14 different tissues or organs across five life stages in both male and female mice.

This extensive dataset enabled us to construct a unified cellular map of organismal aging, identifying >300 distinct cell types and >3000 cellular states. Using this dataset, we characterized sex-dimorphic gene expression patterns shared across organs and cell types as well as cell types with sex-specific molecular programs. Additionally, by clustering >200 cell subtypes undergoing marked aging-associated population changes, we uncovered nonlinear temporal dynamics of aging at the cellular level.

Moreover, we mapped the cross-organ immune landscape of aging, revealing both widespread and organ-specific alterations in immune cells. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent.

CONCLUSION

PanSci provides a comprehensive catalog of aging-related cell population changes, featuring a balanced representation of replicates across sexes, a broader age range, and substantially larger cell numbers compared with existing studies. Our data suggest that aging, at the cellular level, progresses through dynamic changes rather than a simple linear trajectory.

By identifying >200 distinct cellular states with marked aging-related changes, we demonstrate the potential of scalable single-cell genomic techniques to uncover key cellular targets for therapeutic innovations aimed at restoring cellular functions and rejuvenating systemic biological processes in aging and diseases. ..."

From the editor's summary and abstract (2):

"Editor’s summary

Aging atlases have been generated for multiple organisms, but they are often restricted to capturing the transcriptional landscape across cells.

Lu et al. created a single-cell chromatin accessibility atlas in mice for 21 tissues over three age time points ... They combined this atlas with a previous gene expression atlas of aging and found many changes in cellular composition and chromatin accessibility with aging.

Changes occurred across cell types, but immune cells in particular showed diverging patterns with aging, and the authors were able to trace these patterns to particular transcription factor motifs within the peaks. Many of these changes were sex specific, reinforcing the importance of using diverse samples in such endeavors. ...

Structured Abstract

INTRODUCTION

Aging is the leading risk factor for many diseases. This association underscores the potential of therapies targeting the aging process itself to delay or prevent age-related diseases. Substantial advances in single-cell genomics have enabled the profiling of alterations in aging. However, these analyses typically focus on transcriptomics and overlook the impact of chromatin landscapes.

RATIONALE

Single-cell assay for transposase-accessible chromatin using sequencing (ATAC-seq), which analyzes genome-wide chromatin accessibility at the single-cell level, has enabled the mapping of the cell type–specific chromatin landscape in a range of mammalian tissues.

With a further optimized version of single-cell ATAC-seq by combinatorial indexing (EasySci-ATAC), we investigated aging-associated changes in cell populations and chromatin changes across the entire organism, aiming to identify aging-associated noncoding regions and their corresponding cell types.

RESULTS

In this study, we applied EasySci-ATAC to profile chromatin accessibility in more than 10 million nuclei across 21 tissue types from mice spanning three age groups (1 month, 5 months, and 21 months). We detected a total of 1.3 million cis-regulatory elements and identified cell type–specific usages of them.

We reported aging-associated population dynamics of 536 tissue-level main cell types and 1828 finer-grained subtypes. In broadly distributed cell types, we observed coordinated expansion or depletion of the same subtype in multiple organs.

At the molecular level, we identified extensive chromatin reprogramming with aging, including changes in the accessibility of individual peaks and certain transcription factor motifs, and linked them to expression changes of putative target genes.

Moreover, we detected extensive sexual dimorphism, including age-conserved, sex-specific chromatin states for the same cell types and age-sex interaction effects at both proportional and molecular levels.

CONCLUSION

Our organism-level single-cell chromatin accessibility atlas illuminates how aging remodels cellular composition and regulatory regions of multiple tissues.

In addition to many highly tissue-specific changes, we uncovered coordinated cellular and molecular dynamics that are shared across different organs, including immune remodeling, broad depletion of functional cell types, the emergence of inflammation-related states, and sex-dependent trajectories.

By cataloging these changes, we offer a resource for understanding the molecular logic of aging and for guiding therapeutic strategies aimed at preserving or restoring youthful tissue states. ..."

Why Aging May Be a Program, Not a Breakdown | Quanta Magazine "By deciphering the molecular signatures of millions of mouse cells, Junyue Cao has found that aging is not haphazard wear and tear but rather a “remodeling of the cell society.”"

A panoramic view of cell population dynamics in mammalian aging (1, no public access, only cited 94 times which is low for a paper that was first published March 2024 as preprint)

A Panoramic View of Cell Population Dynamics in Mammalian Aging (1, preprint, open access)

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging (2, no public access, cite 14 times)

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging (2, preprint, open access)

Cellular architecture of organismal aging.

An organism-wide single-cell atlas of chromatin accessibility reveals cellular dynamics and epigenomic remodeling during aging.

Breakdown of immune cells' interaction is key driver in aging and the liver is a major source

Good news!

"Two immune cell types’ contact plays a major role in aging. Blocking a hormone’s influence on one of those cell types halted mice’s age-associated decline in multiple organs."

"... A study in mice and human cells by Stanford Medicine researchers pins much of the blame on a particular type of immune cell's increasing inability, with advancing age, to gobble up another immune cell type. ...

So-called tissue-resident macrophages appear to be central coordinators of age-related organ decline. Blocking a single receptor on these cells preserved the youthfulness of multiple organs in mice including the brain, heart, skeletal and heart muscle, liver, spleen, bone marrow, kidney, and colon. The receptor binds specifically to a hormone known to cause inflammation and pain in humans as well as mice.

In mice, selectively disabling this receptor exclusively on tissue-resident macrophages prevented chronic-inflammation-driven disorders of age including frailty, excessive fat accumulation and heart trouble; it also substantially slowed cognitive decline ...

Immune cells produce hormones called prostaglandins. One of the five varieties of prostaglandin, called PGE2, can exert diverse effects on a cell, depending on which type of surface receptor is expressed on that cell’s surface.

Of the various subtypes of receptors for PGE2, one designated EP2 is highly pro-inflammatory. Tissue-resident macrophages are loaded with EP2.

Infection, injury and toxic chemicals including the ones produced by our aging bodies increase PGE2 output. As the 2021 Nature paper showed, that output grows substantially as we grow older. So does the concentration of EP2 on tissue-resident macrophages. ...

bioengineered a mouse in which, at a time of the scientists’ choosing, the gene that’s a recipe for EP2 gets deleted — but only in tissue-resident macrophages. The subsequent disappearance of EP2 from these cells, the new study proves, reinvigorated the neutrophil-devouring process that PGE2 undermines. ...

older mice whose EP2-encoding gene had been deleted at 4 to 6 months of age (their “teenage” years).

The scientists identified 71 proteins, found in blood, whose levels were significantly altered in older normal mice. Of those proteins, 59 stayed at youthful levels in older mice whose tissue-resident macrophages lacked EP2. Many of these proteins originated in the liver.

“The liver is one of the body’s most tissue-resident-macrophage-enriched organs and a major contributor to aging-related changes in blood chemistry,” ... “It’s the central organ determining the body’s metabolic rate.”

Smoldering senescent neutrophils, the study showed, accumulated in normal old mice’s livers, spleens and bone marrow — and, to a lesser extent, in all the many other bodily organs the researchers looked at.

But the organs of older mice lacking EP2 on their tissue-resident macrophages retained the lower neutrophil numbers of youth. These mice looked younger, leaner and more physically fit compared with control littermates. They evidenced less visceral fat and greater muscle mass. Their performance on tests of multiple organs’ function equaled that of young mice.

EP2 deletion reduced inflammation in the blood, liver, colon, heart, kidney and hippocampus (a brain region tightly tied to memory and navigation ability) in the older mice. Their speed, balance and forelimb grip strength resembled that of young animals.

Reducing EP2 action in older mice also preserved their memory capabilities. They could thread their way through a maze or recall previously encountered objects almost as well as younger mice — and far better than similarly old mice in whose tissue-resident macrophages EP2 remained functional. ..."

From the abstract of the Perspective:

"Human aging is asynchronous. Cells, tissues, and organs deteriorate at different rates, an unevenness that may help explain the differential aging trajectories of people.

Elucidating both the overlapping and distinct biological pathways that contribute to cell-tissue-organ aging could guide strategies to promote health longevity. ...

Tan et al. (1) report that the oxylipin prostaglandin E2 (PGE2) undermines the capacity of tissue-resident macrophages (TRMs) from clearing out old, and hence damaging, neutrophils in aging organs. 

n a mouse model, this housekeeping process can be restored if PGE2 action is blocked. The implication is that organ aging is not fixed but may be shaped by specific interventions that slow the decline."

From the editor's summary and abstract:

"Editor’s summary

Increased inflammation is associated with aging and is implicated in decreased function in aging tissues.

Tan et al. explored changes in older tissue-resident macrophages and investigated how these cells may contribute to aging phenotypes in mice ... 

They found that signaling by the lipid messenger prostaglandin E2 was increased in these cells. In various mouse tissues, preventing an increase in tissue-resident macrophages helped to maintain mitochondrial function and limited other deleterious effects of aging. Tissue-resident macrophages help to reduce inflammation by removing apoptotic and damaged cells.

One consequence of inhibiting prostaglandin E2 signaling was restored clearance of senescent neutrophils. These results emphasize the possible roles of macrophages and neutrophil clearance in tissue disfunction during aging.  ...

Structured Abstract

INTRODUCTION

Aging is accompanied by parallel functional decline across organs, but the cellular drivers remain unclear.

Tissue-resident macrophages (TRMs), long-lived cells that comprise 60 to 90% of macrophages in major organs, maintain homeostasis through efferocytosis of apoptotic and senescent cells.

Neutrophils, the most abundantly produced and shortest-lived leukocytes (more than 100 billion generated daily in humans), require continuous TRM clearance; uncleared aged neutrophils release proteases and extracellular traps that damage tissues and propagate aging. TRMs express the prostaglandin E2 (PGE2) receptor EP2, which suppresses macrophage metabolism and phagocytosis in aging. Whether impaired TRM efferocytosis drives the accumulation of senescent neutrophils that promote organ aging and whether inhibition of EP2 signaling can restore this process, remain unknown.

RATIONALE

We studied aged mice in which EP2 signaling on TRMs was selectively reduced, either genetically (TRM-specific EP2 deletion) or pharmacologically, to define how TRM dysfunction shapes organ-wide aging.

TRMs are long-lived gatekeepers of tissue homeostasis, and EP2 offers a tractable target because its activity increases in aged macrophages and suppresses their metabolic and phagocytic function.

Using complementary genetic and pharmacological approaches, we tested whether restoring TRM function reverses organ aging and identified which efferocytic substrate is most affected. The same design also defined the molecular step at which EP2 acts within TRMs and extended our findings to aged human tissues.

RESULTS

In aged mice, TRM-specific EP2 deletion restored mitochondrial fitness and immune homeostasis, and reversed cognitive decline, frailty, sarcopenia, adiposity, and cardiac dysfunction toward youthful states.

Plasma proteomics identified the liver as a major source of age-associated immune changes.

Single-cell RNA-seq of mouse liver and multiorgan flow cytometry revealed accumulation of senescent CXCR4+ neutrophils across efferocytic organs in aging. These cells exhibited the senescence-associated secretory phenotype (SASP), DNA damage response activation, cell cycle inhibitor induction, NETosis, and anti-apoptosis programs, and were efficiently cleared following EP2 deletion. Liver multiplex imaging localized paracrine stress to parenchymal cells neighboring senescent neutrophils.

Ex vivo efferocytosis assays showed that aged TRMs were most impaired in clearing senescent neutrophils relative to apoptotic substrates, with both functions restored by EP2 deletion or pharmacologic antagonism.

Mechanistically, EP2 signaling suppressed integrin-dependent stabilization of senescent neutrophils on TRMs and downstream engulfment.

Analyses of human liver and heart datasets revealed conserved EP2 up-regulation in aged TRMs, enrichment of senescent neutrophils, and reduced TRM–neutrophil interactions.

CONCLUSION

This work identifies EP2 signaling in TRMs as a central regulator of organ-wide aging through its control of senescent neutrophil clearance, reframing aging as a failure of active cellular clearance rather than passive degeneration. With age, neutrophils acquire senescence-associated features, and their accumulation drives tissue injury through two converging mechanisms: intrinsic degranulation and NETosis, and extrinsic paracrine stress on neighboring parenchymal cells. Pharmacological inhibition of EP2 restores TRM efferocytic capacity and promotes clearance of senescent neutrophils, positioning EP2 antagonism as a tractable therapeutic strategy for age-related organ and functional decline."

Breakdown of immune cells' interaction is key driver in aging, study finds

Breakdown of immune cells’ interaction is key driver in aging, study finds (original news release)

Tidying up aging organs (Perspective, no public access)

Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging (no public access)

Tissue-resident macrophage (TRM) clearance of senescent neutrophils is restored by EP2 deletion or inhibition to limit organ aging.

Unprecedented view inside live stem cells reveals aging process and loss of regenerative capacity

Amazing stuff!

"Scientists have developed a powerful new technique that allows them to observe how individual cells manufacture proteins during aging, offering an unprecedented glimpse into the hidden molecular activity of stem cells in living tissue. ...

What scientists saw was the intricate choreography within stem cells and how those molecular dance steps slow and change with age. The team of Swiss scientists has concluded that the process of aging reshapes how skin stem cells manufacture proteins. ..."

From the highlights and abstract:

"Highlights

• In vivo single-cell ribosome profiling monitors tissue-wide translational landscapes

• RNase I-generated footprints reveal robust triplet periodicity in vivo

• Tissue-wide mapping of translational efficiencies across epidermal cell types

• Aging drives selective translational induction of AP-1 subunits in stem cells

Summary

Somatic stem cells are characterized by their low overall protein-synthesis rates, a feature implicated in driving their stemness. However, how aging reshapes the translational landscape of stem cells remains poorly understood.

Here, we present an in vivo single-cell ribosome profiling strategy to monitor tissue-wide translational landscapes of the epidermis during aging.

By implementing ribosomal elongation-inhibited cell isolation and switching to RNase I, we expand the applicability of single-cell ribosome profiling to in vivo systems and facilitate the evaluation of triplet periodicity, a hallmark of high-quality data.

Leveraging this strategy, we document the in vivo translational landscapes of the major epidermal cell types, outline cell-type-specific translational efficiencies, and identify a pronounced translational reprogramming of AP-1 subunits specifically in aged epidermal stem cells. Our study illustrates the power of in vivo single-cell ribosome profiling to map cell-type-specific translational programs and offers a scalable strategy for tissue-wide interrogation of translational landscapes."

Unprecedented view inside live stem cells reveals aging process and loss of regenerative capacity

In vivo single-cell ribosome profiling reveals cell-type-specific translational programs during aging (open access)

Graphical abstract

Scientists Map Aging Across the Body of a Short-Lived Fish

Amazing stuff!

"Studying aging takes time. That’s why neuroscientists studying how brains age turn to thumb-sized fish called killifish. Within just four to six months, the fish hatch, grow to maturity, spawn and die. Their compressed lifespan has made the fish a favorite for research on this inevitable process.

Now, a team ... has created a comprehensive atlas of aging in killifish. By sequencing gene activity across 12 tissues at six life stages in male and female fish, they have documented progressive molecular changes in detail as they unfold across the fish’s body. ...

In humans, immune cells are produced in the bone marrow. In fish, that role falls to the front portion of the kidney. By examining gene activity in this organ, the researchers found a pattern reminiscent of what has been observed in aging mammals, including humans. Markers associated with B and T cells, the immune system’s precision defenders, declined with age. Meanwhile, evidence of immune cells that participate in broader inflammatory responses increased.

Interestingly, this shift was much more pronounced in females than in males. ..."

From the abstract:

"Aging is associated with progressive tissue dysfunction, leading to frailty and mortality. Characterizing aging features, such as changes in gene expression and dynamics, shared across tissues or specific to each tissue, is crucial for understanding systemic and local factors contributing to the aging process.

We performed RNA sequencing on 13 tissues at six different ages in male and female African turquoise killifish, the shortest-lived vertebrate that can be raised in captivity.

This comprehensive, sex-balanced ‘atlas’ dataset revealed varying strength of sex–age interactions across killifish tissues and age-altered genes and biological pathways that are evolutionarily conserved in mice and humans.

We discovered a female-biased myeloid shift with age in the killifish hematopoietic organ, developed tissue-specific ‘transcriptomic clocks’ and identified biomarkers predictive of chronological age.

We showed the importance of sex-specific clocks for selected tissues, validated the tissue clocks with an independent transcriptomic dataset and used them to evaluate different lifespan interventions in the killifish.

Our work provides a comprehensive resource for studying aging dynamics across tissues in the killifish, a powerful vertebrate aging model."

Scientists Map Aging Across the Body of a Short-Lived Fish "A new atlas of aging in the killifish tracks how organs change over time, revealing processes implicated in Alzheimer’s and Parkinson’s diseases. The study also creates AI-driven tools for predicting the biological age of different tissues."

Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish (open access)

Fig. 1: A multi-tissue killifish transcriptomic aging atlas reveals shared and tissue-specific age effects on different tissues.

Standard brain scans can reveal the signs of and the speed of ageing and determine a person's biological clock

Good news! This appears to be a faster version of an existing biomarker of the pace of aging.

"Telltale features in standard brain images can reveal how quickly a person is ageing. In a study of more than 50,000 brain scans, researchers found that features such as the thickness of the cerebral cortex — a region responsible for language and memory — can predict how quickly a person’s ability to think and remember will decline with age.

The study is part of efforts to develop ‘clocks’ that determine a person’s biological age. “Imaging offers unique, direct insights into the brain’s structural ageing, providing information that blood-based or molecular biomarkers alone can’t capture,”..."

"... Pivotal features include the thickness of the cerebral cortex — a region that controls language and thinking — and the volume of grey matter that it contains. These and other characteristics can predict how quickly a person’s ability to think and remember will decline with age, as well as their risk of frailty, disease and death. ..."

From the abstract:

"To understand how aging affects functional decline and increases disease risk, it is necessary to develop measures of how fast a person is aging. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain magnetic resonance imaging, that is, the Dunedin Pace of Aging Calculated from NeuroImaging (DunedinPACNI).

Exporting this measure to the Alzheimer’s Disease Neuroimaging Initiative, UK Biobank and BrainLat datasets revealed that faster DunedinPACNI predicted cognitive impairment, accelerated brain atrophy and conversion to diagnosed dementia.

Faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases and mortality in older adults.

When compared to brain age gap, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a next-generation brain magnetic resonance imaging biomarker that can help researchers explore aging effects on health outcomes and evaluate the effectiveness of antiaging strategies."

Nature Briefing: Translational Research

How fast are you ageing? Ordinary brain scans reveal the pace "Images hold clues to risk of dementia and various age-related diseases."

DunedinPACNI estimates the longitudinal Pace of Aging from a single brain image to track health and disease (open access)

Fig. 1: Schematic overview of the study methods.

An omega-3 a day keeps the ageing away (combined with Vitamin D and regular physical exercise)

Why is the debate over food supplements so controversial for decades in Western countries?

"Omega-3 and vitamin-D supplements, taken over the course of years, might slow biological ageing, according to a new study. Results of a trial of people aged over 70 showed that a combination of the two supplements daily and 30 minutes of exercise three times a week over three years reduced biological ageing — ageing measured at a molecular level — by three to four months. The reduction sounds small, but can translate to important public-health benefits such as a reduction in the prevalence of some age-related health conditions ..."

"... The study analysed data from the DO-HEALTH trial on the effects of supplements and exercise in older people, that took place across five European countries from 2012 to 2014. The researchers reviewed data on more than 700 people aged 70 or over who were given either a placebo or omega-3, vitamin D and exercise alone or in combination. All the participants were from Switzerland and around half were healthy, with no major chronic illnesses or disabilities.

Blood samples taken from participants at the start and end of the study were analysed using four biological clocks. These measure the extent of biological ageing on the basis of additions and deletions of methyl groups to the DNA. ...

One of those clocks, called PhenoAge, showed that older people avoided several months of biological ageing over 3 years by taking 1 gram of polyunsaturated omega-3 fatty acids, derived from algae, with additive benefits from taking vitamin D (2,000 international units per day) and engaging in 30 minutes of exercise 3 times a week. Together, the 3 treatments reduced biological ageing by 2.9–3.8 months. ..."

From the abstract:

"While observational studies and small pilot trials suggest that vitamin D, omega-3 and exercise may slow biological aging, larger clinical trials testing these treatments individually or in combination are lacking.

Here, we report the results of a post hoc analysis among 777 participants of the DO-HEALTH trial on the effect of vitamin D (2,000 IU per day) and/or omega-3 (1 g per day) and/or a home exercise program on four next-generation DNA methylation (DNAm) measures of biological aging (PhenoAge, GrimAge, GrimAge2 and DunedinPACE) over 3 years.

Omega-3 alone slowed the DNAm clocks PhenoAge, GrimAge2 and DunedinPACE, and 

all three treatments had additive benefits on PhenoAge.

Overall, from baseline to year 3, standardized effects ranged from 0.16 to 0.32 units (2.9–3.8 months).

In summary, our trial indicates a small protective effect of omega-3 treatment on slowing biological aging over 3 years across several clocks, with an additive protective effect of omega-3, vitamin D and exercise based on PhenoAge."

Nature Briefing: Translational Research

Omega-3 supplements slow biological ageing "The anti-ageing effect was even greater when combined with vitamin D and exercise."

Individual and additive effects of vitamin D, omega-3 and exercise on DNA methylation clocks of biological aging in older adults from the DO-HEALTH trial (open access)

Fig. 3: Treatment effects of vitamin D, omega-3 and SHEP individually and in combination on changes in DNAm-based surrogate biomarkers of plasma proteins based on GrimAge.

Why our biological clock ticks: Research reconciles major theories of aging

Amazing stuff! This could be a breakthrough!

"... describe a never-before-seen link between the two most accepted explanations: random genetic mutations and predictable epigenetic modifications. The latter, also known as the epigenetic clock theory, has been widely used by scientists as a consistent, quantitative measure of biological aging. ...

"Major research institutions and companies are betting on turning back the epigenetic clock as a strategy to reverse the effects of aging, but our research suggests that this may only be treating a symptom of aging, not the underlying cause,” ...

There are two prevailing theories about the relationship between aging and DNA. The somatic mutation theory suggests that aging is caused by the accumulation of mutations, permanent changes in our DNA sequence that occur randomly.

The epigenetic clock theory suggests that aging occurs due to the accumulation of epigenetic modifications, minor changes to the chemical structure of DNA that do not alter the underlying sequence, but instead change which genes are on or off. Unlike mutations, epigenetic modifications can also be reversed in some cases. ...

To answer this fundamental question, researchers analyzed data from 9,331 patients catalogued in the Cancer Genome Atlas and the Pan-Cancer Analysis of Whole Genomes. By comparing genetic mutations to epigenetic modifications, they found that mutations were predictably correlated with changes in DNA methylation, one type of epigenetic modification. They found that a single mutation could cause a cascade of epigenetic changes across the genome, not just where the mutation occurred. Using this relationship, the researchers were able to make similar predictions of age using either mutations or epigenetic changes. ...

“Our study demonstrates for the first time that epigenetic changes are intricately and predictably tied to random genetic mutations.” ..."

From the abstract:

"DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates.

In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases.

This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life."

Why our biological clock ticks: Research reconciles major theories of aging

Why Our Biological Clock Ticks: Research Reconciles Major Theories of Aging (original news release) "Two prominent explanations for aging are not so different after all; results call current anti-aging strategies into question"

Somatic mutation as an explanation for epigenetic aging (no public access)

Somatic mutation as an explanation for epigenetic aging (prepring, open access)

Key players in brain aging: New research identifies age-related damage on a cellular level

Good news! One day, we will be able to counter the effects of aging!

"Largest study on brain aging points to possible connections between diet, inflammation, and brain health

Scientists ... identified specific cell types in the brain of mice that undergo major changes as they age, along with a specific hot spot where many of those changes occur. ...

Sensitive cells: Scientists discovered dozens of specific cell types, mostly glial cells, known as brain support cells, that underwent significant gene expression changes with age. Those strongly affected included microglia and border-associated macrophages, oligodendrocytes, tanycytes, and ependymal cells.

Inflammation and neuron protection: In aging brains, genes associated with inflammation increased in activity while those related to neuronal structure and function decreased. ...

Aging hotspot: Scientists discovered a specific hotspot combining both the decrease in neuronal function and the increase in inflammation in the hypothalamus. The most significant gene expression changes were found in cell types near the third ventricle of the hypothalamus, including tanycytes, ependymal cells, and neurons known for their role in food intake, energy homeostasis, metabolism, and how our bodies use nutrients. This points to a possible connection between diet, lifestyle factors, brain aging, and changes that can influence our susceptibility to age-related brain disorders. ..."

From the abstract:

"Biological ageing can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Mammalian brains consist of thousands of cell types, which may be differentially susceptible or resilient to ageing.

Here we present a comprehensive single-cell RNA sequencing dataset containing roughly 1.2 million high-quality single-cell transcriptomes of brain cells from young adult and aged mice of both sexes, from regions spanning the forebrain, midbrain and hindbrain.

High-resolution clustering of all cells results in 847 cell clusters and reveals at least 14 age-biased clusters that are mostly glial types. At the broader cell subclass and supertype levels, we find age-associated gene expression signatures and provide a list of 2,449 unique differentially expressed genes (age-DE genes) for many neuronal and non-neuronal cell types.

Whereas most age-DE genes are unique to specific cell types, we observe common signatures with ageing across cell types, including a decrease in expression of genes related to neuronal structure and function in many neuron types, major astrocyte types and mature oligodendrocytes, and an increase in expression of genes related to immune function, antigen presentation, inflammation, and cell motility in immune cell types and some vascular cell types.

Finally, we observe that some of the cell types that demonstrate the greatest sensitivity to ageing are concentrated around the third ventricle in the hypothalamus, including tanycytes, ependymal cells, and certain neuron types in the arcuate nucleus, dorsomedial nucleus and paraventricular nucleus that express genes canonically related to energy homeostasis.

Many of these types demonstrate both a decrease in neuronal function and an increase in immune response. These findings suggest that the third ventricle in the hypothalamus may be a hub for ageing in the mouse brain. Overall, this study systematically delineates a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal ageing that will serve as a foundation for the investigation of functional changes in ageing and the interaction of ageing and disease."

Key players in brain aging: New research identifies age-related damage on a cellular level  - Allen Institute

Brain-wide cell-type-specific transcriptomic signatures of healthy ageing in mice (open access)

This image shows non-neuronal brain cells called tanycytes. They are illuminated and color coded according to their depth in the hypothalamus brain of a mouse and are one of the cell types in the mouse brain that show a large number of gene transcripts changing with age.

Fig. 1: Transcriptomic cell types in young adult and aged mouse brains.

Studying Ovaries to Understand How We All Age

Amazing stuff!

"Ovaries are the fastest aging organ in the body, but the least studied organ in aging research.

The impact of aging ovaries on a woman’s fertility are well known, but aging ovaries—which shrink from the size of a kiwi to a kidney bean—also have much wider impacts on a woman’s health in the later decades of life. The earlier the ovaries age, the more likely a woman is to develop heart disease, dementia, depression, glaucoma, and other diseases, and die earlier.

“The ovary is an endocrine organ and influences aging in the entire body ...

“By delaying ovarian aging, we could live longer and healthier lives,” she says. ...

In our latest research, we compared ovaries in women in their 20s versus 40s or 50s, and the big surprise was that there’s nothing special about how ovaries age. The same genetic programs and molecular signals you see in an old brain or heart or kidney in your 60s, you see in this tiny organ in your 40s.

The good news is that means geroprotective drugs, which delay aging in animals, could be used to delay aging in the ovary. ..."

From the abstract:

"The ovary is the first organ to age in the human body, affecting both fertility and overall health. However, the biological mechanisms underlying human ovarian aging remain poorly understood.

Here we present a comprehensive single-nuclei multi-omics atlas of four young (ages 23–29 years) and four reproductively aged (ages 49–54 years) human ovaries. Our analyses reveal coordinated changes in transcriptomes and chromatin accessibilities across cell types in the ovary during aging, notably mTOR signaling being a prominent ovary-specific aging pathway. Cell-type-specific regulatory networks reveal enhanced activity of the transcription factor CEBPD across cell types in the aged ovary.

Integration of our multi-omics data with genetic variants associated with age at natural menopause demonstrates a global impact of functional variants on gene regulatory networks across ovarian cell types. We nominate functional non-coding regulatory variants, their target genes and ovarian cell types and regulatory mechanisms. This atlas provides a valuable resource for understanding the cellular, molecular and genetic basis of human ovarian aging."

Studying Ovaries to Understand How We All Age | Columbia University Irving Medical Center "New findings from Columbia's Yousin Suh suggests ovarian aging has lessons for us all."

Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses (open access)

Fig. 2: Aging alters ovarian cellular composition and affects the transcriptional activity of pathways involved in the hallmarks of aging across cell types.

Key players in brain aging: New research identifies age-related damage on a cellular level

Good news! Closing in on the fountain of youth!

"Largest study on brain aging points to possible connections between diet, inflammation, and brain health.

Scientists ... have identified specific cell types in the brain of mice that undergo major changes as they age, along with a specific hot spot where many of those changes occur. ...

Aging hot spot: Scientists discovered a specific hot spot combining both the decrease in neuronal function and the increase in inflammation in the hypothalamus. The most significant gene expression changes were found in cell types near the third ventricle of the hypothalamus, including tanycytes, ependymal cells, and neurons known for their role in food intake, energy homeostasis, metabolism, and how our bodies use nutrients. This points to a possible connection between diet, lifestyle factors, brain aging, and changes that can influence our susceptibility to age-related brain disorders.  ..."

From the abstract:

"Biological ageing can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Mammalian brains consist of thousands of cell types, which may be differentially susceptible or resilient to ageing.

Here we present a comprehensive single-cell RNA sequencing dataset containing roughly 1.2 million high-quality single-cell transcriptomes of brain cells from young adult and aged mice of both sexes, from regions spanning the forebrain, midbrain and hindbrain. High-resolution clustering of all cells results in 847 cell clusters and reveals at least 14 age-biased clusters that are mostly glial types.

At the broader cell subclass and supertype levels, we find age-associated gene expression signatures and provide a list of 2,449 unique differentially expressed genes (age-DE genes) for many neuronal and non-neuronal cell types. Whereas most age-DE genes are unique to specific cell types, we observe common signatures with ageing across cell types, including a decrease in expression of genes related to neuronal structure and function in many neuron types, major astrocyte types and mature oligodendrocytes, and an increase in expression of genes related to immune function, antigen presentation, inflammation, and cell motility in immune cell types and some vascular cell types.

Finally, we observe that some of the cell types that demonstrate the greatest sensitivity to ageing are concentrated around the third ventricle in the hypothalamus, including tanycytes, ependymal cells, and certain neuron types in the arcuate nucleus, dorsomedial nucleus and paraventricular nucleus that express genes canonically related to energy homeostasis. Many of these types demonstrate both a decrease in neuronal function and an increase in immune response. These findings suggest that the third ventricle in the hypothalamus may be a hub for ageing in the mouse brain. Overall, this study systematically delineates a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal ageing that will serve as a foundation for the investigation of functional changes in ageing and the interaction of ageing and disease."

Key players in brain aging: New research identifies age-related damage on a cellular level

Key players in brain aging (original news release) "New research identifies age-related damage on a cellular level"

Brain-wide cell-type-specific transcriptomic signatures of healthy ageing in mice (open access)

Fig. 1: Transcriptomic cell types in young adult and aged mouse brains.

Fig. 6: Decreased neuronal function and increased immune activity as common signatures of ageing across brain cell types.

Newly discovered mechanism reveals NAD's role in aging and disease

Good news!

"... "Therefore, dysregulated NAD levels are involved in aging processes as well as many pathologies ranging from cancer to diabetes and neurodegenerative diseases. And the reason for this is that it holds a key position in both energy metabolism and the regulation of vital functions," ...

Based on their new findings, the team of researchers believes that excessive consumption of mitochondrial NAD might constitute a key factor leading to dysfunctional cellular powerhouses and thus aging-associated diseases. ..."

From the abstract:

"The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption.

To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged.

Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected."

Newly discovered mechanism reveals NAD's role in aging and disease

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+ (no public access)

Proposed model for the cooperation of SLC25A51 and NMNAT3 to buffer cellular NAD+ fluctuations.

Novel biomarker IL-23R catches aging cells in the act

Good news!

"Mayo Clinic researchers have identified interleukin-23 receptor (IL-23R) as a significant biomarker of cellular senescence and aging in both mice and humans. Experiments show that IL-23R levels in the bloodstream increase with age and can decrease, reflecting senescent cell clearing, with senolytic therapies. ...

Scientists have been searching for a biomarker that reliably estimates the levels of active senescent cells in the body. If found, this biomarker could inform clinical interventions, potentially intervening before disease conditions present themselves.

In the study "IL-23R is a senescence-linked circulating and tissue biomarker of aging," published in Nature Aging, researchers sought to identify senescence-related biomarkers and measure their responsiveness to different therapeutics in mice of various ages.

The team tested 92 plasma proteins through the Olink Target 96 Mouse Exploratory panel and ultimately analyzed 67 (25 were excluded due to low or no detection).

Tissues, including kidney, liver, spleen, cerebral cortex, adipose and lung, were examined with real-time PCR for 21 gene expressions related to senescence secretions and inflammation markers. ...

Analyses showed that three of the tested plasma proteins, IL-23R, CCL5 and CA13, displayed age-related alterations in circulation and tissues, indicating potential biomarker marker viability.

Age-dependent increases in IL-23R and CCL5 were reversed by senolytic treatment, and CA13 levels, which normally decline with age, were restored to more youthful levels.

Researchers identified IL-23R as the most promising plasma protein biomarker due to its obvious and consistent association with aging across multiple tissue parameters. IL-23R increased with age in both mice and humans and had a robust change response to senolytic interventions. ..."

From the abstract:

"Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden."

Novel biomarker catches aging cells in the act

Researchers discover an aging and inflammation biomarker (original news release)

IL-23R is a senescence-linked circulating and tissue biomarker of aging (open access)

... researchers found that the gene expression of Il23r (depicted in red), which increases in aged blood at the protein level, is present in aged kidney and is associated with the senescence marker p16 (shown in green). When IL-23R signaling is overactive, it can lead to inflammation and tissue damage. ...

Fig. 1: Conserved and distinct plasma proteins are altered by age in female and male mice.

Fig. 3: Age-related changes in plasma proteins are reverted by short-term senotherapeutic interventions.