Fight Aging! Newsletter, April 10th 2023

UNITY Biotechnology's lead asset, UBX1325, failed to show non-inferiority to Regeneron's anti-VEGF drug aflibercept in a Phase II wet age-related macular degeneration (wAMD) trial. This sent the biotech's shares tumbling 46% in premarket trading on Monday. The 24-week data are from the Part A portion of the proof-of-concept Envision study of UBX1325, a Bcl-xL inhibitor. The trial involved 51 patients with wAMD who received either two 10 mcg doses of UBX1325 at week zero and week four or anti-VEGF agent aflibercept 2 mg every eight weeks.

The trial used the Early Treatment Diabetic Retinopathy Study (ETDRS) to assess the therapies, which revealed an early and unexpected visual gain of 3.5 ETDRS letters with aflibercept, according to Unity. The 3.5-letter gain with aflibercept was mostly maintained for the study's duration. UBX1325 monotherapy, meanwhile, reduced letters by 0.8 from baseline.

Patients were already receiving aflibercept when they enrolled in the trial, but benefit from the therapy was not optimal, according to the press release. More than half (52%) of patients who received UBX1325 did not require anti-VEGF treatment throughout the 24 weeks of the trial, UNITY reported.

UNITY Biotechnology, Inc. ("UNITY"), a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced results from Part A of the Phase 2 ENVISION study of UBX1325 in patients with wet age-related macular degeneration (AMD) who were not achieving optimum benefit with their ongoing anti-VEGF therapy. UBX1325 treatment generally maintained visual acuity for 6 months (change of -0.8 ETDRS letters from baseline), with a majority of patients not requiring any anti-VEGF rescue. Patients in the every 8-week aflibercept arm had an early and unexpected gain of 3.5 letters at week 2 which was mostly maintained for the duration of the study. As a result of the strength on the control arm, the study did not meet the non-inferiority threshold compared to aflibercept through 24 weeks.

"Maintenance of visual acuity in hard-to-treat patients with active disease after withdrawal of their anti-VEGF therapy suggests that UBX1325 had an active treatment effect in wet AMD. We continue to be impressed with the durability of effect of UBX1325 in this patient population. Following a full analysis of ENVISION results, we will assess and optimize our resource allocation for future development of UBX1325. In the weeks ahead we will provide an update on Part B of the ENVISION study, and importantly, share 48-week data from the Phase 2 BEHOLD DME study. In DME, UBX1325 showed strong evidence of biologic activity and improvement in visual acuity - and, as a result, we plan to initiate a Phase 2b study in the second half of this year."

Many theories of why we age have been proposed, including damaged-based and programmatic theories, with the former currently more widely accepted and studied. Most damage-based theories postulate that inefficient repair mechanisms result in singular or multiple, and often interacting, forms of damage accumulation. Although damage can be broadly defined as any change that affects function, here I refer more specifically to molecular damage hypothesized to drive ageing, such as by-products of metabolism, unwanted chemical modifications, and other types of molecular damage affecting crucial cellular components like the genome, telomeres, mitochondria, and proteins. By contrast, programmatic theories argue that ageing results from predetermined mechanisms encoded in the genome, rather than stochastic damage accumulation.

The concept of information in biology has a long history, and biological systems can be seen as highly complex information systems. Likewise, the idea that ageing could be linked to information decay or loss has been proposed, in particular in the context of the information theory of ageing. According to this theory, loss of genetic or epigenetic information with age, driven by DNA damage, is the primary cause of ageing. One hypothesis is that errors accrue in the DNA, corrupting the information in the genome and ultimately disrupting tissue homeostasis and causing ageing. More broadly, the idea that errors or damage to one or more biological types of hardware, including the DNA, accumulate and drive the process of ageing has been prevalent for decades. By hardware I encompass all elements of biological systems, including organs, tissues and the basic unit of life, the cell, and its structures (mitochondria, telomeres, proteins, DNA, and so on), most of which have at some point been hypothesized to be important in ageing.

What if, however, the processes that cause ageing are not a product of inevitable molecular damage but rather intrinsic features of the software? In this context, I define software as the genetic program, the DNA code that orchestrates how a single cell becomes an adult human being capable of reproducing, ultimately our evolutionary purpose. Herein, I present and explore the hypothesis that perhaps ageing is not a result of inevitable wear and tear or accumulated molecular damage in the hardware but rather that ageing is caused by design flaws in the software itself. I discuss manipulations of ageing and how they support this hypothesis, acknowledge exceptions, and lastly, propose areas of future study.

Current oncogenic theories state that tumors arise from cell lineages that sequentially accumulate (epi)mutations, progressively turning healthy cells into carcinogenic ones. While those models found some empirical support, they are little predictive of intraspecies age-specific cancer incidence and of interspecies cancer prevalence. Notably, in humans and lab rodents, a deceleration (and sometimes decline) of cancer incidence rate has been found at old ages. Additionally, dominant theoretical models of oncogenesis predict that cancer risk should increase in large and/or long-lived species, which is not supported by empirical data.

Here, we explore the hypothesis that cellular senescence could explain those incongruent empirical patterns. More precisely, we hypothesize that there is a trade-off between dying of cancer versus dying of other ageing-related causes. This trade-off between organismal mortality components would be mediated, at the cellular scale, by the accumulation of senescent cells. In this framework, damaged cells can either undergo apoptosis or enter senescence. Apoptotic cells lead to compensatory proliferation, associated with an excess risk of cancer, whereas senescent cell accumulation leads to ageing-related mortality.

To test our framework, we build a deterministic model that first describes how cells get damaged, undergo apoptosis, or enter senescence. We then translate those cellular dynamics into a compound organismal survival metric also integrating life-history traits. We address four different questions linked to our framework: can cellular senescence be adaptive, do the predictions of our model reflect epidemiological patterns observed among mammal species, what is the effect of species sizes on those answers, and what happens when senescent cells are removed? Importantly, we find that cellular senescence can optimize lifetime reproductive success. Moreover, we find that life-history traits play an important role in shaping the cellular trade-offs.

A key but unresolved issue in the study of human mortality at older ages is whether mortality is being compressed (which implies that we may be approaching a maximum limit to the length of life) or postponed (which would imply that we are not). We summarize historical mortality data in 19 currently-industrialized countries by birth cohort using a variant of the Gompertz mortality law, and find that it fits cohort mortality data extremely well. Using this law, we identify the youngest age at which individuals in each cohort reach an assumed mortality plateau, which we call the Gompertzian Maximum Age (GMA). We find that over much of the period covered by our data, there was no increase in the GMA. Historical improvements in life expectancy were therefore largely the result of mortality compression. We demonstrate, however, that there have been episodes where the GMA increased. The presence of these episodes of mortality postponement suggests that the maximum length of a human life is not, in fact, fixed.

The first episode of mortality postponement that we identify occurred for cohorts born in the early part of the second half of the 19th century, and was more pronounced for females than for males. Over this period, the GMA increased by around 5 years. We can only speculate as to the causes of this increase, but as the first of these cohorts reached age 50 just after 1900 and the last reached age 100 in 1980, this may be related to a first wave of improvements in public health and medical technology. We identify a second, and much more significant, episode of mortality postponement, which is affecting cohorts born between 1910 and 1950 (so those currently aged between 70 and 110). We estimate that the GMA for these cohorts may increase by as much as 10 years, and remaining life expectancy at age 50 by as much as 8 years, depending on the country.

The timing of these episodes of mortality postponement explain why longevity records have been so slow to increase in recent years - cohorts old enough to have broken longevity records were too old to experience the current bout of postponement - and identifies significant potential for longevity records to rise by the year 2060 as younger cohorts, who did experience it, reach advanced old age. Our results on the division of changes in remaining life expectancy at age 50 across cohorts between compression and postponement are robust to our modelling choices. Likewise, our conclusion that longevity records will likely be broken in the coming decades is also robust to a wide range of possible assumptions. But our predictions of precisely by how much these records will rise, and when, depend on our modelling assumptions, in particular on the maximum mortality rate we assume.

We emphasise further that cohorts born before 1950 will only have the potential to break existing longevity records if policy choices continue to support the health and welfare of the elderly, and the political, environmental and economic environment remains stable. The emergence of Covid-19 and its outsize effect on the mortality of the elderly provides a salutary warning that none of this is certain. If, however, the GMA does increase as the current mortality experience of incomplete cohorts suggests is likely, the implications for human societies, national economies, and individual lives will be profound.

The DNA-repair capacity in somatic cells is limited compared with that in germ cells. It has remained unknown whether not only lesion-type-specific, but overall repair capacities could be improved. Here we show that the DREAM repressor complex, formed by the Dp/Retinoblastoma(Rb)-like/E2F and the MuvB subcomplexes, curbs the DNA-repair capacities in somatic tissues of Caenorhabditis elegans. Mutations in the DREAM complex induce germline-like expression patterns of multiple mechanisms of DNA repair.

Consequently, DREAM mutants confer resistance to a wide range of DNA-damage types during development and aging. Similarly, inhibition of the DREAM complex in human cells boosts DNA-repair gene expression and resistance to distinct DNA-damage types. DREAM inhibition leads to decreased DNA damage and prevents photoreceptor loss in progeroid Ercc1-/- mice. We show that the DREAM complex transcriptionally represses essentially all DNA-repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA-repair capacities.

Alzheimer's disease (AD) predominantly occurs as a late onset (LOAD) form involving neurodegeneration and cognitive decline with progressive memory loss. Risk factors that include aging promote accumulation of AD pathologies, such as amyloid-beta and tau aggregates, as well as inflammation and oxidative stress. Homeostatic glial cell states regulate and suppress pathology buildup; inflammatory states exacerbate pathology by releasing pro-inflammatory cytokines. Multiple stresses likely induce glial senescence, which could decrease supportive functions and reinforce inflammation.

In this perspective, we hypothesize that aging first drives AD pathology burden, whereafter AD pathology putatively induces glial senescence in LOAD. We hypothesize that increasing glial senescence, particularly local senescent microglia accumulation, sustains and drives perpetuating buildup and spread of AD pathologies, glial aging, and further senescence. We predict that increasing glial senescence, particularly local senescent microglia accumulation, also transitions individuals from healthy cognition into mild cognitive impairment and LOAD diagnosis. These pathophysiological underpinnings may centrally contribute to LOAD onset, but require further mechanistic investigation.

In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin.

In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.

We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood-brain barrier (BBB) integrity, and prevented the age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function associated with impaired cognition.

Compared to older controls, senolytic treatments decreased transcription of dentate gyrus genes linked to oxidative stress and immune response, and increased the expression of synaptic genes. However, D + Q had a greater effect on brain transcription categories associated with cellular senescence, decreasing expression of genes linked to apoptosis, regulation of apoptosis, and microglial activation that were not significant for ABT-263 treatment. Dissimilarities associated with brain transcription indicate divergence in central mechanisms, possibly due to differential brain access. Previous work indicates that dasatinib enters the central nervous system to clear senescent cells. In contrast, ABT-263 does not cross the BBB, which may explain differential effects.

Even when a primary tumor is successfully treated, cells that have broken away from the tumor often linger in the body in a dormant state that allows them to evade detection by the immune system for years at a time. Then, after the dormant cells have developed new traits to help them survive, they can wake up and start their runaway growth again. "These tumor cells are not in a supportive environment at the beginning. So they have to adapt and develop their own self-supporting niche until they're ready, eventually, to wake up and start a fast-growing metastasis. The interaction with the person's immune system is very important to this process."

Using mouse models of early-stage metastasis from lung cancer, the research team conducted a genetic screen to look at the activity of genes in the tumor cells that are important for interactions with the host's immune system. That's how they identified the STING pathway - an acronym for stimulator of interferon genes - as a suppressor of metastatic outbreaks. Importantly, the researchers found that STING expression changes across different stages of metastasis. In the dormant stage, STING activity is low - and the dormant cells excel at hiding out from immune defenders. Moving out of the dormant stage and into an awakened, proliferative stage, the metastatic cells start to have increased STING activity. This makes them more vulnerable to attack by the immune system. But cells that survive this bottleneck to generate larger clusters, called macrometastastes, again show reduced STING levels, which makes them more resistant to the immune system.

Using STING activators in conjunction with that window of increased STING activity in the reawakened cancer cells could be an opportunity to help the body's immune defenders destroy them. Indeed, when scientists artificially increased STING signaling in those aggressive metastatic cells, they attracted more immune defenders like natural killer cells and T cells, which swooped in to kill them off. And when the scientists activated STING in mice lacking key immune cells, metastasis still developed - pointing to a critical role for STING in recruiting the immune cells to attack the cancer cells.

As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits. Increases in microglial inflammatory activity are thought to contribute to age-related declines in cognitive functions and to transitions toward mild cognitive impairment (MCI) and Alzheimer's disease (AD). As microglia possess receptors for communicating with the CNS environment, pharmacological therapies targeting these pathways hold potential for promoting homeostatic microglial functions within the aging CNS.

Preclinical and early phase clinical trials investigating the therapeutic effects of pharmacological agents acting on microglia, including reactive oxygen species, TREM2, fractalkine signaling, the complement cascade, and the NLRP3 inflammasome, are currently underway; however, important questions remain unanswered. Current challenges include target selectivity, as many of the signaling pathways are expressed in other cell types. Furthermore, microglia are a heterogenous cell population with transcriptomic, proteomic, and microscopy studies revealing distinct microglial states, whose activities and abundance shift across the lifespan. For example, homeostatic microglia can transform into pathological states characterized by markers of oxidative stress.

Selective pharmacological targeting aimed at limiting transitions to pathological states or promoting homeostatic or protective states, could help to avoid potentially harmful off-target effects on beneficial states or other cell types. In this mini-review we cover current microglial pathways of interest for the prevention and treatment of age-related cognitive decline and CNS disorders of aging focusing on MCI and AD. We also discuss the heterogeneity of microglia described in these conditions and how pharmacological agents could target specific microglial states.

Defining the mechanisms safeguarding cell fate identity in differentiated cells is crucial to improve 1) our understanding of how differentiation is maintained in healthy tissues or altered in a disease state, and 2) our ability to use cell fate reprogramming for regenerative purposes. Here, using a genome-wide transcription factor screen followed by validation steps in a variety of reprogramming assays (cardiac, neural and iPSC in fibroblasts and endothelial cells), we identified a set of four transcription factors (ATF7IP, JUNB, SP7, and ZNF207, collective AJSZ) that robustly opposes cell fate reprogramming in both lineage and cell type independent manners.

Mechanistically, our approach revealed that AJSZ oppose cell fate reprogramming by 1) maintaining chromatin enriched for reprogramming transcription factor motifs in a closed state and 2) downregulating genes required for reprogramming. Finally, knockdown of AJSZ in combination with overexpression of cardiac reprogramming factors Mef2c, Gata4, and Tbx5, collectively MGT, significantly reduced scar size and improved heart function by 50%, by reprogramming fibroblasts into cardiomyocytes, as compared to MGT alone post-myocardial infarction.

Collectively, our study suggests that inhibition of barrier to reprogramming mechanisms represents a promising therapeutic avenue to improve adult organ function post-injury.

The blood vessel-rich tissue in the retina, can be used to track human aging in an aging clock called eyeAge, in a way that is noninvasive, less expensive and more accurate than other aging clocks that are currently available. A growing body of evidence suggests that the microvasculature in the retina might be a reliable indicator of the overall health of the body's circulatory system and the brain. Changes in the eye accompany aging and many age-related diseases including age-related macular degeneration (AMD), diabetic retinopathy, and Parkinson's and Alzheimer's disease. Ophthalmologists can often detect early symptoms of AIDS, chronic high blood pressure and certain tumors in the eyes, a utility that is not surprising given that any subtle changes in the vascular system first appear in the smallest blood vessels, and capillaries in the retina are among the smallest in the body.

But subtle changes in these small blood vessels often go undetected by even the most sophisticated instruments, necessitating the use of deep learning, an effort spearheaded by Google Research. Researchers from Google and elsewhere developed models to predict diabetic retinopathy from retinal images and have gone on to use retinal images to identify at least 39 eye diseases including glaucoma, diabetic retinopathy, and AMD, as well as non-eye diseases such as chronic kidney disease and cardiovascular disease. Google researchers trained and tuned the model for eyeAge using their well-studied EyePACS data set which involves more than 100,00 patients and applied it to patients from the UK Biobank, which involved more than 64,000 patients.

"This type of imaging could be really valuable in tracking the efficacy of interventions aimed at slowing the aging process. The results suggest that potentially, in less than one year we should be able to determine the trajectory of aging with 71% accuracy by noting discernable changes in the eyes of those being treated, providing an actionable evaluation of geroprotective therapeutics. Our study emphasizes the value of longitudinal data for analyzing accurate aging trajectories. Through EyePACS longitudinal dataset involving multiple scans from individual people over time our results show a more accurate positive prediction ratio for two consecutive visits of individual rather than random, time-matched individuals."

Using a multi-modal, single cell approach, we generated cell composition and transcriptional profiles from the peripheral blood mononuclear cells (PBMCs) of 7 centenarians using CITE-seq. We integrated this novel data set with publicly available single cell RNA-seq datasets of aging and longevity across the human lifespan to characterize cell type composition and gene expression profiles unique to centenarians. The peripheral blood immune cell repertoire of individuals is known to change with age. Previous transcriptional studies have shown decreases in lymphocytes and increases in myeloid cells with age, which we also observed in the peripheral blood of centenarians. However, in addition to these common changes across aging, our analysis identified patterns of immune cell profiles and compositional alterations that are unique to centenarians.

We observed expected shifts in the composition of centenarians' PBMCs from non-cytotoxic (e.g., naive CD4+ T cells and memory CD4+ T cells) to cytotoxic lymphocytes (e.g., cytotoxic CD4+ T cells) that have been observed previously in studies of human longevity. Similarly, the decrease of naive B cells with aging and longevity has also been reported previously. However, we also discovered novel compositional patterns of extreme old age including aging-related changes (e.g. a significant increase of CD14+ monocytes in older age that continues in the centenarian group), centenarian-specific changes (e.g. myeloid dendritic cells and plasmacytoid dendritic cells display no significant change among the three younger age groups but a unique, significant decrease occurs in extreme longevity), and aging-specific changes independent of extreme longevity (e.g. a significant increase of CD16+ monocytes in older age that then decreases in the centenarian age group).

The extent to which these unique patterns in centenarians are the drivers of extreme longevity or just the consequence of having reached an extreme old age remains an open question, since not everything we see in centenarians is necessarily important to reach extreme old ages. Additional data are needed to understand the effect of these patterns on human longevity. Overall, these findings display age-related changes in composition and transcription in both lymphocyte and myeloid cell types that collectively reflect immunocompetent profiles that may in part account for centenarians' ability to reach extreme ages.

TAR DNA binding protein 43 kDa (TDP-43) plays an important role in several essential cell functions. However, TDP-43 dysfunction has been implicated in the development of various brain diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Recent investigations into the individual components of TDP-43 pathology show how broader TDP-43 dysfunction may precede these disease end states, and therefore could help to explain why TDP-43 dysfunction continues to be implicated in a rapidly expanding category of neurodegenerative diseases.

TDP-43 pathology is usually characterized by insoluble, hyperphosphorylated and ubiquinated aggregates of TDP-43 in the cytoplasm, nucleus, and cell processes of neurons and glia. Mislocalization of TDP-43 within cellular compartments is also characteristic of the pathology. Normally TDP-43 is tightly auto-regulated and is almost entirely located in the nucleus. Consequently, depletion of TDP-43 in the nucleus, in association with abnormally high levels in the cytoplasm, is considered to be pathological. Indeed, TDP-43 mislocalization alone appears capable of causing mRNA instability, impaired gene regulation, mitochondrial dysfunction, impaired protein turnover, among other issues. However, the underlying causes of TDP-43 mislocalization and aggregation remain unclear.

The literature reviewed in this article suggests that dysregulation of TDP-43 initiated by some environmental and/or genetic insults can lead to a snowballing dysfunction across the cell, involving impaired gene expression, mRNA stability, as well as the function and coordination of those pathways directly regulated by TDP-43. Furthermore, the hallmarks of TDP-43 pathology, such as hyperphosphorylation and insoluble cytoplasmic accumulation of the protein may actually be artifacts of an upstream impairment in TDP-43's normal function.