Fight Aging! Newsletter, September 2nd 2024

First, epigenetic aging in human health should be viewed holistically. The relationship between epigenetic age and health outcomes is often viewed through a narrow lens. Blood epigenetic clocks are predominantly used due to their availability. However, as measured by these clocks, studies and trials frequently focus solely on blood, neglecting broader aging effects on the entire organism. This oversight can lead to exaggerated claims and misconceptions among the public. A younger biological age based on a buccal swab does not necessarily equate to a younger immune system or skeletal muscle composition.

Second, accept the limitations of epigenetic aging clocks. While efforts have been made to develop clocks independent of tissue or cell type, our study demonstrates that entirely eliminating the confounding effects of cell type in epigenetic age acceleration calculation is nearly impossible. Senescence at the cellular level manifests differently across cell types and states, making it challenging to devise a single clock applicable to all cell types. Although universal epigenetic aging marks may exist, modeling them accurately across cell types at the bulk tissue level is complicated by age-related changes in cell composition.

Third, contextualize when interpreting epigenetic aging results. The perception that an accelerated epigenetic age is always detrimental stems from a limited understanding of the clock mechanism. Contrary to this notion, multiple studies have documented beneficial outcomes in specific groups of cancer patients with accelerated epigenetic age. Immune responses play a pivotal role in cancer patient outcomes, and the connection between immune cell composition and epigenetic age established in our study sheds light on how epigenetic age acceleration affects these outcomes, especially in treatments like chemotherapy, radiation therapy, and immunotherapy that influence or rely on the immune system. Moreover, research has revealed significant daily oscillations in epigenetic age, mirroring changes in immune cell composition over the circadian rhythm.

Fourth, model epigenetic biomarkers on biological pathways to avoid black boxes. While direct modeling of DNA methylation changes with age enhances the predictability of biological age, it often obscures specific pathways captured by the algorithm, resulting in black boxes. To mitigate this, further efforts should focus on directly modeling aging and senescence-related pathways for novel biomarkers tracing age. Several markers exemplify the value of this approach. EpiTOC, for instance, functions as a mitotic clock, estimating stem cell divisions. It tracks age and correlates with increased cancer risk, offering insights into the association between cellular aging processes and cancer.

The emergence of Hevolution and the XPRIZE Healthspan is just the latest development in a remarkable phenomenon: a dramatic upsurge in activity in the private sector aimed at developing treatments for aging, fuelled by a heady optimism that the time is nigh. Other examples that involve massive funding to achieve practical outcomes in applied research on aging include the California Life Company (Calico), into which some 2.5 billion has been invested; and Altos Labs, which in 2022 raised 3 billion from investors.

Here we ask the question: what is the basis for this optimism? The last quarter of a century has seen a concerted effort by scientists to understand the fundamental biological mechanisms of aging, and much ground has been covered. How has this informed the recent upswell in commercial activity? We suggest that the latter is an anomaly arising in part from developments within the aging research field a decade ago that were, in some ways, counterproductive. These include the emergence of the so-called geroscience research agenda.

What seems to have happened is the following. Advances in research on the biology of aging that culminated in the 1990s yielded startling implications. It seemed possible not only to understand the fundamental mechanisms of aging, but also to slow them down. These promising prospects led to the aging field becoming bigger and better, thanks to increased funding and the influx of many good scientists. As a result, standards of research grew more rigorous, including critical reassessments of earlier findings. Such careful research over the past two decades has, regrettably, undermined a number of the reasons for earlier optimism. Disappointingly, caloric restriction in rhesus monkeys proved not to have the same remarkable effects as those seen in rodents. Growth hormone defects that extend lifespan in mice were found not to do so in humans.

With the dwindling likelihood that humans possess the plasticity in aging seen in shorter-lived animals, and the failure of existing theories of aging, how should one further pursue research? Here two possible approaches may be envisaged. On the one hand, scientists could renew their efforts to develop an effective theoretical framework with the capacity to explain diverse phenomena of aging. On the other hand, research could focus on translating existing theoretical claims and experimental observations into therapeutic trials - preclinical or clinical. The pursuit of this strategy in the early 2010s marked the emergence of the geroscience agenda.

In the past, this strategy of prioritizing translational research in the absence of a good understanding of the basic science has sometimes proved successful, aided by brute force and serendipity. There are, however, also numerous instances where such trial-and-error approaches failed, sometimes involving investment of billions. The reader may pick their own examples. Unquestionably, for translational research to yield useful, practical applications, at least some level of scientific understanding is required. At issue is judging when the time is ripe to move from basic to translational research, particularly where large investments of money and effort are involved. The oddest thing about the translational geroscience approach is its combination of pessimism about understanding aging, and optimism about translational research. Arguably, the inverse is more realistic.

Billionaires sit on vast resources, but they don't seem to be ready to massively invest in longevity yet. But it shouldn't be just about the money. This is literally about life and death.

You're absolutely right, but that's just not the way they're viewing it. You could say that all of us put our money in three different buckets. There's a bucket for money that will be used to make more money. Another one is for money that will be used for family, enjoyment, vacations, and so on. And the last one is for helping people. Unfortunately, for most people, that last bucket is the smallest by orders of magnitude.

I think it's not just about philanthropy. It should also be driven by egoistic considerations. Maybe there's a place for a fourth bucket, where you help humanity, but you also help yourself. After all, today, death is pretty inescapable whether you're a billionaire or a construction worker. Even more so than, say, climate change.

It seems obvious to me. Why aren't people acting in their own self-interest? This thing should hit every bucket. I'm going to invest in longevity because it's going to help me, my family, and humanity, and it will also allow me to feel better, to have a happier life. And it's also a huge business opportunity, right? The only reason that's not hitting is that people don't believe it yet. We have been so indoctrinated about the inevitability of death!

I try to change it, by writing books about this. My mission is to help the public create a longevity mindset, which is based on the realization that the technology to enable us to extend the healthy human lifespan is coming online now, in the decade ahead. And if you believe that in the next ten years, we're going to significantly extend the human healthspan, and you can have access to it if you're in good health, then, logically, you'd want to do everything you can to remain in the best health possible. I want people to change the way they think about healthspan and longevity and what's possible for them. Because your mindset is the most powerful tool that you have. If you believe it, you're going to change your behavior.

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer.

Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors.

Combined, our data documents spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed.

Usually, aging is a gradual process characterized (in humans and mouse models) by molecular biomarkers such as a decrease in leukocyte telomere length, decreased levels of IGF-1, and increased inflammation. Several molecular mechanisms have been purported to regulate aging and determine lifespan - many of which have been linked to p53 tumor suppressor activities. In low or high-stress conditions, p53 binds to several target genes - including those that encode PML, PAI-1, and DEC1 - which then induce cellular senescence. The link between aging and its ability to push cells to senescence is of particular interest to this study. In a senescent state, a damaged cell resists apoptosis and ceases to replicate. An accumulation of these cells triggers the aging process by creating a senescence-associated secretory phenotype (SASP) which creates a chronic inflammatory microenvironment. It has been shown that a programmed clearance of senescent cells delays aging phenotypes.

While p53 consensus sequences for most of these targets have been elucidated, few studies have explored regulatory mechanisms and structural features of p53 that could be implicated in organismal aging. Residual changes in the DNA-binding domain of several orthologs of p53 in Cetaceans have been linked to longevity. This supports findings that p53-mediated cellular senescence could be mediated directly by DNA binding. Additionally, there has been an extension exploration of the role of the mouse MDM2 gene in the aging process of mice. MDM2 is the most well-studied negative inhibitor of p53 tumor suppressive activity; disruption of the MDM2-p53 axis accelerates aging in some mice, suggesting the importance of the MDM2-p53 axis to the aging process.

However, p53's link to organismal aging may not be easily explainable just by the MDM2-p53 axis. MDM2 has only minor regulatory effects on the levels of p53 in the naked mole rat. And, interestingly, the naked mole rat lives an average of 30 years compared to an average of 2-4 years for most rodents. This is thought to be due in part to a hyperstable p53 - the source of this stability remains largely unknown. In another case, the African elephant despite being predisposed to cancer due to prolonged UV-radiation and large body mass lives comparably long lives and displays a significantly lower frequency of cancer when compared to humans. The unique presence of 20 copies of p53 in their genome is thought to be responsible for this.

This study seeks to elucidate, structurally and mechanistically, p53's roles in longevity. Through a relative evolutionary scoring (RES) algorithm, we quantify the level of evolutionary change in the residues of p53 across organisms of varying average lifespans in six taxonomic orders. Secondly, we used the PEPPI protein-protein interaction predictor to assess the likelihood of interaction between p53 - or p53-linked proteins - and known senescence-regulating proteins across organisms in the orders Primates and Perciformes. Our RES algorithm found variations in the alignments within and across orders, suggesting that mechanisms of p53-mediated regulation of longevity may vary. PEPPI results suggest that longer-lived species may have evolved to regulate induction and inhibition of cellular senescence better than their shorter-lived counterparts. With experimental verification, these predictions could help elucidate the mechanisms of p53-mediated cellular senescence, ultimately clarifying our understanding of p53's connection to aging in a multiple-species context.

The focus of Jean Hébert's scientific work is the neocortex, the outer part of the brain that looks like a pile of extra-thick noodles and which houses most of our senses, reasoning, and memory. The neocortex is "arguably the most important part of who we are as individuals, as well as maybe the most complex structure in the world." There are two reasons Hébert believes the neocortex could be replaced, albeit only slowly. The first is evidence from rare cases of benign brain tumors, like a man described in the medical literature who developed a growth the size of an orange. Yet because it grew very slowly, the man's brain was able to adjust, shifting memories elsewhere, and his behavior and speech never seemed to change - even when the tumor was removed. That's proof, Hébert thinks, that replacing the neocortex little by little could be achieved "without losing the information encoded in it" such as a person's self-identity.

The second source of hope, he says, is experiments showing that fetal-stage cells can survive, and even function, when transplanted into the brains of adults. For instance, medical tests underway are showing that young neurons can integrate into the brains of people who have epilepsy and stop their seizures. "It was these two things together - the plastic nature of brains and the ability to add new tissue - that, to me, were like, 'Ah, now there has got to be a way.'"

One challenge ahead is how to manufacture the replacement brain bits, or what Hébert has called "facsimiles" of neocortical tissue. During a visit to his lab Hébert described plans to manually assemble chunks of youthful brain tissue using stem cells. These parts, he says, would not be fully developed, but instead be similar to what's found in a still-developing fetal brain. That way, upon transplant, they'd be able to finish maturing, integrate into your brain, and be "ready to absorb and learn your information." To design the youthful bits of neocortex, Hébert has been studying brains of aborted human fetuses 5 to 8 weeks of age. He's been measuring what cells are present, and in what numbers and locations, to try to guide the manufacture of similar structures in the lab.

Hébert's ideas appear to have gotten a huge endorsement from the US government. Hébert has proposed a 110 million project to ARPA-H to prove his ideas in monkeys and other animals, and that the government "didn't blink" at the figure. ARPA-H confirmed this week that it had hired Hébert as a program manager.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons.

We applied single-cell and spatial transcriptomics, lineage-tracing, and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1.

Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.

While humans and most vertebrates can only regenerate parts of certain organs or limbs, other animal groups have far stronger regeneration mechanisms. This ability is made possible by pluripotent or multipotent stem cells, which can form (differentiate) almost all cell types of the body. The sea anemone Nematostella vectensis is also highly regenerative: it can reproduce asexually by budding and also shows no signs of ageing, which makes it an interesting subject for stem cell research. However, researchers have not yet been able to identify any stem cells in these animals.

"By combining single-cell gene expression analyses and transgenesis, we have now been able to identify a large population of cells in the sea anemone that form differentiated cells such as nerve cells and glandular cells and are therefore candidates for multipotent stem cells."

These potential stem cells express the evolutionarily highly conserved genes nanos and piwi, which enable the development of germ cells in all animals, including humans. By specifically mutating the nanos2 gene using the CRISPR gene scissors, the scientists were also able to prove that the gene is necessary for the formation of germ cells in sea anemones. It has also been shown in other animals that this gene is essential for the production of gametes. This proves that this gene function emerged around 600 million years ago and has been preserved to this day. In future studies, researchers now want to investigate which special properties of the sea anemone's stem cells are responsible for its potential immortality.

Immunoglobulin G (IgG) is an important serum glycoprotein and a major component of antibodies. Glycans on IgG affect the binding of IgG to the Fc receptor or complement C1q, which in turn affects the biological activity and biological function of IgG. Altered glycosylation patterns on IgG emerge as important biomarkers in the aging process and age-related diseases. Key aging-related alterations observed in IgG glycosylation include reductions in galactosylation and sialylation, alongside increases in agalactosylation, and bisecting GlcNAc.

Understanding the role of IgG glycosylation in aging-related diseases offers insights into disease mechanisms and provides opportunities for the development of diagnostic and therapeutic strategies. This review summarizes five aspects of IgG: an overview of IgG, IgG glycosylation, IgG glycosylation with inflammation mediation, IgG glycan changes with normal aging, as well as the relevance of IgG glycan changes to aging-related diseases. This review provides a reference for further investigation of the regulatory mechanisms of IgG glycosylation in aging-related diseases, as well as for evaluating the potential of IgG glycosylation changes as markers of aging and aging-related diseases.

The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues.

Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8+ T cells and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8+ T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors.

Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.

Until relatively recently, treatment strategies aiming at the scavenging of amyloid-β (Aβ) by passive immunization with antibodies have largely failed to show a significant deceleration of cognitive decline in clinical studies, in fact raising concerns about the amyloid hypothesis. Similar discouraging observations were made in Alzheimer's mouse models. There are several possible explanations for the general failure of these approaches, most prominently an inadequate timing of the therapeutic intervention after the brain has already undergone irreparable damage.

Moreover, anti-Aβ treatment at very early stages of development had positive outcomes in mouse models of amyloidosis. Thus, before Aβ plaque formation, the prevention of extracellular Aβ accumulation involving the use of γ-secretase inhibitors can effectively abolish neuronal hyperactivity. This is relevant because a variety of studies in mice and humans have established that neuronal hyperactivity is probably the earliest form of neuronal dysfunction in the diseased brain.

To untangle the conflicting results on the effectivity of Aβ removal obtained from previous mouse studies, we applied here an alternative approach based on the direct intracerebral application of Aβ-binding anticalins (Aβ-anticalins). Anticalins exhibit very high target affinities and, in contrast to antibodies, a low immunogenic potential. We demonstrate that an Aβ-anticalin can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages.

In this context, exercise is a powerful "geroprotector" that is well-recognized to extend the human health span. However, the relationship between physical fitness and biological age, based on the DNA methylation (DNAm) aging clock, is poorly understood. Most previous studies investigated the relationship between physical activity and DNAm aging clocks based on questionnaires and accelerometers using a molecular epidemiological approach. Theoretically, physical activity and fitness differ, with physical fitness considered the result of exercise, which is planned and regular physical activity. Considering that various health outcomes can be strongly associated with fitness, especially cardiorespiratory fitness (CRF), rather than with physical activity, CRF can be a stronger geroprotector than physical activity. Therefore, in the field of geroscience, it can be valuable to investigate the relationship between CRF and the DNAm aging clock and determine fitness reference values for delaying aging.

We attempted to determine the relationship between CRF and various lifestyle-related factors associated with biological aging based on DNAm aging clocks. We found that CRF was negatively related to epigenetic age acceleration, even after adjusting for confounders (chronological age, smoking, and alcohol consumption), and that maintenance of CRF above a reference value (i.e., 22.7 mL/kg/min) was associated with lower age acceleration. Collectively, these findings suggest that although the relative contribution of CRF to biological aging is relatively low when compared with lifestyle-related variables, such as smoking, the maintenance of CRF is associated with delayed biological aging in older males.

The central concern of exercise scientists is determining the causal relationship between CRF and biological aging. Several cross-sectional studies, including ours, have only demonstrated the relationship between physical activity, physical fitness, and biological aging; however, the causal relationship between them remains elusive. To prove a causal relationship, it is necessary to conduct longitudinal studies that track age-related changes in both CRF and DNAm aging clocks, as well as endurance exercise training intervention studies. In mouse studies, late-life exercise training could delay epigenetic aging of skeletal muscle. In humans, exercise training reportedly leads to epigenetic patterns toward a younger profile. Another study has reported that the number of subjects with higher baseline levels of epigenetic age acceleration decreased after exercise training

The brain is a metabolically vulnerable organ suffering acute functional decline when fuel delivery is compromised. We previously showed that central nervous system nerve terminals rely on efficient activity-dependent up-regulation of ATP synthesis to sustain function and undergo abrupt synaptic collapse when this process fails. Reduced fuel delivery to the brain is correlated with aging and is an early predictor of eventual neurological dysfunction, suggesting that as fuel delivery becomes compromised, synaptic function becomes increasingly vulnerable to genetic metabolic lesions. Parkinson's disease (PD) has long-been thought to be, in part, driven by metabolic vulnerability of dopamine (DA) neurons of the substantia nigra pars compacta (SNc) as two of the earliest identified genetic drivers of PD, PARK2 and PARK6, when mutated, compromise the integrity of mitochondria.

Several recent discoveries point to a critical but unexpected outsized role of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) in protecting neurons against neurological impairment. PGK1, the first ATP-producing enzyme in glycolysis, catalyzes the sixth step in this 10-step enzymatic cascade. A chemical screen of a subset of FDA-approved drugs capable of suppressing cell death identified terazosin (TZ) as a weak (~4%) off-target activator of PGK1. TZ was subsequently shown to confer significant protection in numerous models of PD (mouse, rat, Drosophila, and human induced pluripotent stem cells), implying that contrary to expectations, PGK1 activity is a critical modulator of glycolytic throughput. Clinical use of TZ for treatment of benign prostate hyperplasia provided data for a retrospective analysis, which showed that prolonged use of TZ reduced the risk of developing PD by up to ~37% compared to tamsulosin, whose chemical structure differs significantly from TZ but has the same molecular target.

These data all predict that PGK1 activity is a crucial leverage point in neuronal bioenergetic control and that bioenergetic deficits, in turn, underpin many forms of PD. Here, we demonstrate that PGK1 is the rate-limiting enzyme in axonal glycolysis and that modest changes in PGK1 activity accelerate neuronal ATP production kinetics capable of reversing the synaptic deficit driven by the PARK20 mutation. We identified PARK7/DJ-1, the PD-associated molecular chaperone, as a necessary gene for PGK1 to up-regulate ATP production as loss of PARK7/DJ-1 itself led to deficits in neuronal glycolysis that impaired the ability of PGK1 up-regulation to provide protection. We showed that increasing PGK1 abundance in vivo offered strong protection against striatal DA axon dysfunction. These data strongly support the idea that PGK1 serves as a critical lever arm in controlling axonal bioenergetics.

The balance between scarring and successful tissue regeneration is strongly influenced by immune cells recruited to the wound site, and many researchers are interested in finding ways to boost the activity of immune cell types that promote regeneration while inhibiting the activity of immune cells that promote tissue scarring. Recent studies have suggested that molecules secreted by parasitic worms might modulate the host's immune system in ways that promote tissue regeneration.

In a new study, researchers investigated a protein called TGF-β mimic (TGM) that is produced by Heligmosomoides polygyrus, a parasitic roundworm that lives in the intestines of mice and other rodents. The researchers found that daily topical applications of TGM accelerated the closure of skin wounds in mice. Moreover, TGM treatment reduced the formation of scar tissue while enhancing skin regeneration. For example, unlike untreated animals, TGM-treated mice were able to form new hair follicles within the wounded region of the skin.

The researchers determined that TGM works by binding to a signaling protein, called the TGF-β receptor, that is found on the surface of many cell types in mice and humans, including immune cells. TGM treatment appears to stimulate the recruitment of immune cells known as macrophages into wounds and reprograms them to promote tissue regeneration.

Aging significantly impacts the hematopoietic system, reducing its regenerative capacity and ability to restore homeostasis after stress. Mouse models have been invaluable in studying this process due to their shorter lifespan and the ability to explore genetic, treatment, and environmental influences on aging. However, not all aspects of aging are mirrored between species. This review compares three key aging biomarkers in the hematopoietic systems of mice and humans: myeloid bias, telomere attrition, and epigenetic clocks.

Myeloid bias, marked by an increased fraction of myeloid cells and decreased lymphoid cells, is a significant aging marker in mice but is scarcely observed in humans after childhood. Conversely, telomere length is a robust aging biomarker in humans, whereas mice exhibit significantly different telomere dynamics, making telomere length less reliable in the murine system. Epigenetic clocks, based on DNA methylation changes at specific genomic regions, provide precise estimates of chronological age in both mice and humans. Notably, age-associated regions in mice and humans occur at homologous genomic locations. Epigenetic clocks, depending on the epigenetic signatures used, also capture aspects of biological aging, offering powerful tools to assess genetic and environmental impacts on aging.

Taken together, not all blood aging biomarkers are transferable between mice and humans. When using murine models to extrapolate human aging, it may be advantageous to focus on aging phenomena observed in both species. In conclusion, while mouse models offer significant insights, selecting appropriate biomarkers is crucial for translating findings to human aging.