Can you slow the aging process? Study reveals which interventions might help

Good news! Again, lifestyle improvements (healthier diet, less stress, more physical exercise and so on) are confirmed to be very strong when it comes to healthy aging and long life. The way one ages is to a large extent a personal choice.

Notice this study is focused on epigenetic aging, which may or may not be a narrow focus of the complex process of aging.

"... Using a new class of DNA-based blood tests, they found that lifestyle interventions and certain drug treatments indeed appear to slow the aging process, while over-the-counter supplements don’t have much effect. ...

For their analysis, the researchers primarily used a type of blood-based biomarker known as epigenetic clocks, which estimate epigenetic or biological age by measuring the pattern of methyl groups (basic chemical structures that act like tags) attached to a person’s DNA.

As people age, these chemical tags change, previous research has shown. Successful anti-aging interventions can reverse the tags. Computer algorithms are then able to use the changes observed in these tags to estimate a person’s epigenetic “age.” ...

The researchers tested four categories of intervention: pharmacological drugs, lifestyle-based changes, over-the-counter supplements, and medical procedures. They found that lifestyle interventions, such as a combination of a healthy diet (whether it’s Mediterranean, low-carb, or low-fat) and exercise, consistently decreased epigenetic age.

Pharmacologic interventions — including metformin and semaglutide, prescription medications used for metabolic control and weight management, and anti-TNF therapies, which use biologic medications to target an immune system protein that triggers harmful inflammation — decreased epigenetic age the most. (TNF, or tumor necrosis factor, is an immune-system protein that helps fight inflammation-related injury.) ..."

From the abstract:

"Aging biomarkers can potentially allow researchers to rapidly monitor the impact of an aging intervention without the need for decade-spanning trials.

However, before the use of aging biomarkers, such as epigenetic clocks, as surrogate endpoints, their responsiveness to interventions that target aging must be tested.

Here we curate TranslAGE, a harmonized database of 51 public and private longitudinal interventional studies, and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 94 other DNA methylation (DNAm) biomarkers that can help explain the changes observed for each clock.

Using this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers.

For example, clocks trained to predict mortality or pace of aging show the strongest responses across all interventions and show consistent results with one another; 

pharmacological and lifestyle interventions drive the strongest responses from DNAm biomarkers; and the characteristics of the study population and study duration are key factors in determining the responsiveness of DNAm biomarkers to an intervention.

Moreover, clocks with multiple subscores (that is ‘explainable clocks’) provide specificity and greater mechanistic insight into the responsiveness of interventions than single-score clocks.

These findings can help to design future clinical trials by guiding the choice of interventions and of specific subsets of DNAm biomarkers to minimize multiple testing, study duration, study population and sample size, with the eventual aim of uncovering DNAm biomarkers that can be used as surrogate aging endpoints."

Can you slow the aging process? Study reveals which interventions might help | Yale News "A new Yale analysis found that diet, exercise, and some medications can slow the aging process, while over-the-counter supplements appear to have little effect."

Responsiveness of epigenetic aging biomarkers to longevity interventions in humans (open access)

Fig. 1: Current paradigms to study the responsiveness of DNAm biomarkers and their limitations.

Fig. 3: Interventions and their effects on 16 prominent DNAm biomarkers.

Can one parent silence the other’s genes? Natural ‘paramutations’ found in mice

Amazing stuff!

"... The new research ... indicates genes from one parent can sometimes unexpectedly silence those inherited from the other, and that the effect could persist for generations. If the findings extend to humans, they could help explain why some people who carry a disease-causing genetic variant never develop the condition.

The phenomenon, named paramutation, challenges the conventional view of inheritance and had not been shown to naturally occur in mammals. It’s a form of epigenetics, in which chemical modifications to DNA sequences or proteins they wrap around turn genes on or off. In paramutation, through a process scientists don’t fully understand, one copy of a gene can silence the dominant version inherited from the other parent by coating it with methyl groups.

Paramutation’s discovery in mice marks a major shift in how scientists think about epigenetic inheritance in mammals ..."

"... Since its discovery in maize in 1950s, paramutation has been observed in other plants, fruit flies, and nematodes. The effects can be visible.  ...

Until recently, researchers lacked the tools to reliably trace which parent has passed along a particular version of a gene, called an allele. Traditional DNA sequencing didn’t read long sequences of DNA to see the variation needed to distinguish maternal and paternal alleles—the short stretches were often identical, obscuring their origin. But the arrival of long-read sequencing changed that, as researchers could examine enough DNA from a gene at once to link individual alleles to a specific parent. ..."

"... “Non-Mendelian patterns of inheriting epigenetics could be a faster way to acquire diverse or new traits than alterations in the genomic sequence itself, especially in response to environmental pressures,” ..."

From the abstract:

"Epigenetic mechanisms such as genomic imprinting demonstrate that molecular inheritance can deviate from typical Mendelian patterns. Despite this, the intergenerational inheritance of DNA methylation remains poorly understood.

Here we developed a genome-wide approach to study epigenetic inheritance in mice using long-read nanopore sequencing. Using this approach in both liver and muscle, we found that ~93% of autosomal epigenetic inheritance patterns followed Mendel’s laws, primarily driven by cis-acting methylation quantitative trait loci.

However, we also identified extensive non-Mendelian inheritance, including emergent epigenetic inheritance patterns, widespread sex-specific DNA methylation patterns localized to the liver, and five seemingly new autosomal and X-linked imprinted genes.

Notably, we also report an example of naturally occurring intergenerational paramutation, confirmed over strain-specific transposable elements within Capn11 and highly likely at Vps37c.

Overall, an unexpectedly high ~7% of autosomal epigenetic inheritance patterns identified were non-Mendelian, highlighting the importance of epigenetic information in the analysis of inherited traits and disorders."

Can one parent silence the other’s genes? Natural ‘paramutations’ found in mice | Science | AAAS "Odd phenomenon first seen in plants could explain puzzling disease inheritance patterns"

Lab Study Reveals Patterns of Inheritance That Defy Mendel's Laws (original news release)

Non-Mendelian inheritance of DNA methylation patterns in mice (open access)

Fig. 1: Identification and characterization of Mendelian and non-Mendelian epigenetic inheritance patterns.

What changes happen in the aging brain? A comprehensive single-cell atlas to date of epigenetic changes in the aging mouse brain

Very impressive!

"Highlights

• Salk researchers create epigenetic atlas of cell type-specific changes in the aging mouse brain
• The atlas represents eight different brain regions and 36 different cell types, and shows clear epigenetic differences associated with different ages
• The new resource—available publicly on Amazon Web services—can be used to unravel age-related contributions to neurodegenerative diseases like Alzheimer’s, Parkinson’s, and ALS

...

One major mechanistic influence on aging is epigenetic change: the way small chemical tags on top of our base genetic code shift over time to alter gene expression. Salk researchers created the most comprehensive single-cell atlas to date of epigenetic changes in the aging mouse brain, revealing how DNA methylation, genome structure, and gene activity change across brain regions and cell types. The new atlas represents eight brain regions and 36 distinct brain cell types, with over 200,000 single cells profiled across methylation and chromatin conformation assays, plus nearly 900,000 cells captured with spatial transcriptomics. ..."

What changes happen in the aging brain? - Salk Institute for Biological Studies "Salk Institute scientists create atlas of cell type-specific epigenetic changes that occur in the mouse brain as it ages to better understand the basis of neurodegenerative diseases"

Salk researchers used spatial transcriptomics to map where different cell types reside in the mouse brain. Shown are excitatory neurons (left, blue), inhibitory neurons (middle, red), and non-neuronal cells (right, green), color-coded by cell type.

Mapping 'dark' regions of the genome illuminates how cells respond to their environment

Amazing stuff!

"Researchers ... used CRISPR technologies to discover previously unannotated stretches of DNA in the "dark genome" that are responsible for controlling how cells sense and respond to the mechanical properties of their local environment. ..."

"Only 1-2% of our genome encodes for genes. The other 98% of the genome clearly plays an important role in shaping cell identity, response to the environment, and susceptibility to disease, but until recently we didn’t have the tools to probe the function of this ‘dark’ part of our genome,” ...

they made hydrogels that mimic tissues of different stiffness and cultured cells on these gels. The researchers then used sequencing tools to quantify RNA levels and map regions of open chromatin, or accessible DNA, in order to determine changes to gene expression and genome structure in each sample.

“In just 20 hours on the different gels, we observed changes in the levels of thousands of genes and the structure of almost fifty thousand regions of the genome,” ... “This underscores the profound effect of the mechanical microenvironment on cell biology and clarifies how changes in tissue structure can play a significant role in diseases like fibrosis and cancer.” ..."

From the abstract:

"Epigenetic control of gene expression and cellular phenotype is influenced by changes in the local microenvironment, yet how mechanical cues precisely influence epigenetic state to regulate transcription remains largely unmapped.

Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a class of genomic enhancers that responds to the mechanical microenvironment.

These “mechanoenhancers” can be preferentially activated on either soft or stiff extracellular matrix contexts and regulate transcription to influence critical cell functions including apoptosis, adhesion, proliferation, and migration.

Epigenetic editing of mechanoenhancers reprograms the cellular response to the mechanical microenvironment and modulates the activation of disease-related genes in lung fibroblasts from healthy and fibrotic donors.

Epigenetic editing of mechanoenhancers holds potential for precise targeting of mechanically-driven diseases."

Mapping 'dark' regions of the genome illuminates how cells respond to their environment

Mapping ‘Dark’ Regions of the Genome Illuminates How Cells Respond to Their Environment (original news release) "Previously unmapped sections of the genome explain how cells sense their mechanical environment and could open new paths for treating disease"

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness (no public access)

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness (preprint, open access)

Fig. 2.

CRISPRi screening reveals a MYH9 intron 3 mechanoenhancer that regulates MYH9 expression and cell contractility.

Scientists create first map of DNA modification in the developing human brain

Amazing stuff!

"Key takeaways

• A UCLA-led study has created a map of DNA modification in two regions of the brain critical to learning, memory and emotional regulation. The map offers a benchmark for ensuring stem cell-based models accurately replicate human brain development. 
• ... researchers were able to simultaneously analyze two epigenetic mechanisms – DNA methylation and chromatin conformation – that control gene expression on a single-cell basis. 
• Understanding how these regulatory elements act on genes that affect development will help elucidate where genetic variants connect with certain genes, helping to pinpoint the cell types and developmental periods most vulnerable to disorders and diseases.

...
It created the first map of DNA modification in the hippocampus and prefrontal cortex — two regions of the brain critical to learning, memory and emotional regulation. These areas are also frequently involved in disorders like autism and schizophrenia. ...

To produce the map, the research team used a cutting-edge sequencing approach ... called single nucleus methyl-seq and chromatin conformation capture, or snm3C-seq.

This technique enables researchers to simultaneously analyze two epigenetic mechanisms that control gene expression on a single-cell basis: chemical changes to DNA known as methylation and chromatin conformation, the 3D structure of how chromosomes are tightly folded to fit into nuclei. ...

The research team analyzed more than 53,000 brain cells from donors spanning mid-gestation to adulthood, revealing significant changes in gene regulation during critical developmental windows. In capturing such a broad spectrum of developmental phases, the researchers were able to assemble a remarkably comprehensive picture of the massive genetic rewiring that occurs during critical timepoints in human brain development. ..."

From the abstract:

"The human hippocampus and prefrontal cortex play critical roles in learning and cognition, yet the dynamic molecular characteristics of their development remain enigmatic. Here we investigated the epigenomic and three-dimensional chromatin conformational reorganization during the development of the hippocampus and prefrontal cortex, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation generated by single-nucleus methyl-3C sequencing (snm3C-seq3). The remodelling of DNA methylation is temporally separated from chromatin conformation dynamics. Using single-cell profiling and multimodal single-molecule imaging approaches, we have found that short-range chromatin interactions are enriched in neurons, whereas long-range interactions are enriched in glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type development and differentiation, finding putatively causal common variants for schizophrenia strongly overlapping with chromatin loop-connected, cell-type-specific regulatory regions. Our data provide multimodal resources for studying gene regulatory dynamics in brain development and demonstrate that single-cell three-dimensional multi-omics is a powerful approach for dissecting neuropsychiatric risk loci."

Scientists create first map of DNA modification in the developing human brain | UCLA "Findings could help pinpoint cell types most vulnerable to conditions like schizophrenia, autism spectrum disorder"

Temporally distinct 3D multi-omic dynamics in the developing human brain (open access)

Fig. 1 Fig. 1: Profiling of epigenomic and chromatin conformation dynamics during human brain development using snm3C-seq3.

Epigenetics: Can we change our genes?

Recommendable!

In a First, Scientists Fully Wipe a Cell's Memory Before Turning It Into a Stem Cell

Good news! 

"... Now an international team of researchers has gone one better: finding a new way of wiping a cell's memory clean so it can be better reprogrammed as a stem cell. ...

The new method, called transient-naive-treatment (TNT) reprogramming, mimics the reset of a cell's epigenome that happens in very early embryonic development, before and after an embryo implants itself in the uterus wall.

In a series of cell experiments, the researchers showed that TNT reprogramming "effectively erases epigenetic memory", particularly in densely packed regions of DNA – but without deleting other important information imprinted on the genome.

As a result, the reprogrammed cells better resembled embryonic-like stem cells in their function and on a molecular level. ..."

"In a groundbreaking study published today in Nature, Australian scientists have resolved a long-standing problem in regenerative medicine. ... the team developed a new method to reprogram human cells to better mimic embryonic stem cells, with significant implications for biomedical and therapeutic uses. ...

“However, a persistent problem with the conventional reprograming process is that iPS [induced pluripotent stem] cells can retain an epigenetic memory of their original somatic state, as well as other epigenetic abnormalities,” ... “This can create functional differences between the iPS cells and the ES cells they’re supposed to imitate, and specialised cells subsequently derived from them, which limits their use,”. ..."

From the abstract:

"Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS cells and human embryonic stem (hES) cells differ significantly, which affects hiPS cell function. These differences include epigenetic memory and aberrations that emerge during reprogramming, for which the mechanisms remain unknown. Here we characterized the persistence and emergence of these epigenetic differences by performing genome-wide DNA methylation profiling throughout primed and naive reprogramming of human somatic cells to hiPS cells. We found that reprogramming-induced epigenetic aberrations emerge midway through primed reprogramming, whereas DNA demethylation begins early in naive reprogramming. Using this knowledge, we developed a transient-naive-treatment (TNT) reprogramming strategy that emulates the embryonic epigenetic reset. We show that the epigenetic memory in hiPS cells is concentrated in cell of origin-dependent repressive chromatin marked by H3K9me3, lamin-B1 and aberrant CpH methylation. TNT reprogramming reconfigures these domains to a hES cell-like state and does not disrupt genomic imprinting. Using an isogenic system, we demonstrate that TNT reprogramming can correct the transposable element overexpression and differential gene expression seen in conventional hiPS cells, and that TNT-reprogrammed hiPS and hES cells show similar differentiation efficiencies. Moreover, TNT reprogramming enhances the differentiation of hiPS cells derived from multiple cell types. Thus, TNT reprogramming corrects epigenetic memory and aberrations, producing hiPS cells that are molecularly and functionally more similar to hES cells than conventional hiPS cells. We foresee TNT reprogramming becoming a new standard for biomedical and therapeutic applications and providing a novel system for studying epigenetic memory."

Caution: This is a very long article!

In a First, Scientists Fully Wipe a Cell's Memory Before Turning It Into a Stem Cell : ScienceAlert

Scientists find way to wipe a cell’s memory to better reprogram it as a stem cell

Transient naive reprogramming corrects hiPS cells functionally and epigenetically (open access)

Fig. 1: Distinct trajectories of DNA methylation change during human naive and primed reprogramming.

Epigenetics and Aging: The effects of DNA breakage and repair

Recommendable! About longevity and reversing ageing.

Rejuvenation by controlled reprogramming is the latest gambit in anti-aging

Very recommendable! Amazing stuff! This is a long and comprehensive article!

I have little doubt that we are coming closer to finding the fountain of youth! Perhaps, we are only 10-20 years away!

"... a recent surge of investment in ventures seeking to build anti-aging interventions on the back of basic research into epigenetic reprogramming ...
The discovery of the ‘Yamanaka factors’ — four transcription factors (Oct3/4, Sox2, c-Myc and Klf4) that can reprogram a differentiated somatic cell into a pluripotent embryonic-like state — earned Kyoto University researcher Shinya Yamanaka a share of the Nobel prize in 2012. The finding, described in 2006, transformed stem cell research by providing a new source of embryonic stem cell (ESC)-like cells, induced pluripotent stem cells (iPSCs), that do not require human embryos for their derivation. But in recent years, Yamanaka factors have also become the focus for another burgeoning area: aging research. ...
So-called partial reprogramming consists in applying Yamanaka factors to cells for long enough to roll back cellular aging and repair tissues but without returning to pluripotency. Several groups, including those headed by Stanford University’s Vittorio Sebastiano, the Salk Institute’s Juan Carlos Izpisúa Belmonte and Harvard Medical School’s David Sinclair (Table 1), have shown that partial reprogramming can dramatically reverse age-related phenotypes in the eye, muscle and other tissues in cultured mammalian cells and even rodent models by countering epigenetic changes associated with aging. ...
partial reprogramming could be potentially “transformative” when it comes to treating or even preventing age-related diseases ...
the biology of rejuvenation by reprogramming remains enigmatic and opaque, at best. ... “But much more research is needed to dig into the molecular and mechanistic processes that are occurring.” Given that fully reprogrammed iPSCs readily form tumors known as teratomas ...
Yamanaka’s technique, which can even generate biologically youthful stem cells from centenarian donors, has been extensively studied over the past 15 years. ... that most iPSC reprogramming comes down to rewriting epigenetic marks — chemical modifications of the genome, such as DNA and histone methylation, that influence which genes are active or quiescent and that tend to change as cells age. ...
In 2020, ... team reset the epigenome to restore vision in mice using the adeno-associated virus (AAV) vector to deliver three Yamanaka genes ... The expression of the transcription factors in retinal ganglion cells reversed vision loss in mice, promoting axon regeneration after optic nerve injuries or glaucoma in aged mice. Critically, the researchers saw no sign of lost cellular identity, even when the three Yamanaka genes were continuously expressed. ..."

Rejuvenation by controlled reprogramming is the latest gambit in anti-aging Startups are betting that partial reprogramming with Yamanaka factors may lead to age reversal, but hurdles remain.