Fight Aging!

The medical biotechnology and pharmaceutical investment market was always very risk averse, giving rise to the valley of death between preclinical seed funding and early clinical stage funding; there are all too few investors willing to fund companies to move from late preclinical stage to early clinical stage. They would rather let promising companies die out and pick from the few that somehow find funds to run a first clinical trial in human patients than take the risk on a preclinical program. Further, investment is a herd industry, it polarizes to a few hot areas, fads, and sure things. In the recent years of various flavors of poor market environment for biotechnology and pharmaceutical drug development it seems that these tendencies have grown more exaggerated. A sizable fraction of all biotech investment pours into a small number of cellular reprogramming initiatives, a hot area of research and development, while investors have largely retreated from preclinical funding more generally. It will be interesting to see how long this lasts, as it is clearly unsustainable for every initiative in the field other than reprogramming.

This year alone has seen sizable funding devoted to Retro Bio and NewLimit for reprogramming efforts, though in fairness Retro Bio does have a number of other programs on the go. Life Biosciences raised a relatively smaller but still sizable amount in the grand scheme of things for their clinical trials in reprogramming. Couple all of this to the even greater funding still possessed by Altos Labs, and it seems fair to say that partial epigenetic reprogramming is the one area of aging-related biotechnology that needs no further assistance from patient advocates and other folk. Over the next decade or so we should expect the development community to establish answers to all of the fundamental questions regarding the construction of viable therapies based on reprogramming.

It remains strange to me that partial reprogramming captured the market and the interest in this way rather than senolytic therapies to clear senescent cells, given that senolytics were first on the scene by some years, and senolytic research continues to boast a far larger and more impressive portfolio of animal data for reversal of age-related disease and dysfunction. There is no accounting for how things turn out sometimes. Once enough funding flocks to a cause, there is a tipping point, and its popularity becomes a self-fulfilling prophecy. The funding carves a channel for more funding.

No limits: NewLimit lands $435m ahead of human trials

NewLimit believes it has found a way to help older liver cells behave more like younger ones. That idea sits within a growing area of longevity science known as epigenetic reprogramming. The company has raised $435 million in a Series C financing round led by Founders Fund, with participation from Thrive Capital, Greenoaks, Quiet Capital and existing investors including Kleiner Perkins, Eli Lilly Ventures and Human Capital. More notably, the company says it plans to bring its first age-reprogramming medicine into human clinical trials next year - a milestone it once thought was more than a decade away. Just a year ago, NewLimit closed a $130 million funding round and was still talking about the long road toward a clinic-ready therapy. Then something changed. According to NewLimit, a promising candidate emerged from the company's research platform far sooner than expected, prompting the company to accelerate its plans.

Retro Biosciences: Next Phase

Today, we're announcing the initial close of our next financing round at a pre-money valuation of $1.8 billion, led by 4P Capital alongside a group of investors who believe Retro is uniquely positioned to translate the biology of aging into a new generation of medicines. In three years, Retro moved from its first lab to a clinical candidate. In 15 months, that candidate RTR242 went from indication selection to first-in-human dosing. Alongside that progress, we've built cell therapy, tissue reprogramming, and AI-enabled protein engineering programs, all designed to support a growing pipeline of therapeutics targeting the underlying drivers of aging and age-related disease.

Everyone develops atherosclerotic plaque that narrows and weakens blood vessel walls in later life. A sizable fraction of all human mortality derives from the consequences of that plaque, such as rupture of unstable plaque to cause a stroke or heart attack. The maladaptive formation of blood clots within or attached to the plaque structure greatly reduces the stability of these structures, and is an important contribution to mortality. Here, researchers show that cells driven into a senescent state by the toxic plaque environment generate the circumstances that provoke inappropriate clot formation in and around an atherosclerotic plaque. Of note, other work has suggested that those same senescent cells may be structurally important to a plaque, and removing them may also cause loss of plaque stability. After a certain point, it becomes hard to resolve the issues a plaque presents. Here, as elsewhere in medicine, prevention is far more desirable than resolution.

Researchers have discovered a molecular pathway that drives certain stressed or aging cells to become abnormally active, causing inflammation inside blood vessel plaques. This results in disturbed blood flow and high-risk lesions that can lead to blood clots that cause heart attacks or strokes. The researchers studied senescent cells, which are stressed or aging cells that have stopped dividing but don't die. They discovered that losing key regulatory proteins, LATS1 and LATS2, in these cells activates the CD38 enzyme, which reprograms how these cells use energy and makes them more unstable. This leads to inflammation and an increased risk of blood clot formation inside plaques, a process known as atherothrombosis.

The researchers used advanced molecular profiling on preclinical models to show how endothelial cells - the cells lining blood vessels - change with the loss of LATS1/2 proteins, which usually help with healthy cell stabilization. Removing LATS1/2 in endothelial cells caused them to become senescent but also abnormally active. This led to instability, leaky vessels, inflammation, abnormal vessel growth and plaques that could form clots, all of which are pro-thrombotic features.

Further analyses showed that these senescent cells had a dramatic increase in CD38 levels, highlighting their potential role as key drivers of this hybrid state. Preclinical models demonstrated that overexpressing CD38 rewired the metabolic pathways and energy sources for endothelial cells, leading them to consume enough additional energy to drive inflammation. This destabilized plaques and led to the formation of blood clots. Inhibiting CD38 reversed these effects both in vitro and in vivo.

Link: https://www.mdanderson.org/newsroom/research-newsroom/researchers-uncover-how-aging-cells-may-trigger-heart-attacks-and-strokes.h00-159856134.html

Microglia are innate immune cells resident in the brain, responsible for defense against pathogens, destruction of senescent and potentially cancerous cells, and assistance with regeneration and tissue maintenance. In recent years, increasing attention has been given to changes in the behavior of microglia, particularly increased inflammatory signaling, as a contributing cause of age-related neurodegenerative conditions. Here, researchers make use of modern omics technologies to assess distinct states in subpopulations of microglia that associate with the presence or absence of Alzheimer's disease in older individuals. This sort of research sets the stage for later efforts to alter the behavior of microglia in order to improve brain function, such as via clearance of damaged or inflammatory microglia, or forcing overly inflammatory microglia into a more regenerative pattern of behaviors.

Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs.

This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.

Link: https://doi.org/10.1038/s41591-026-04393-8