LongeCityNews Last Updated: 19 September 2025 - 01:48 AM

Many proteins can form transient aggregates, in which misfolding or chemical decoration allows solid clumps of protein to precipitate from solution and disrupt cellular biochemistry. A much smaller number of proteins can form persistent aggregates, however, and this unfortunate mechanism is an important contributing cause of a variety of age-related conditions. This is particularly the case in the brain. Consider amyloid-β, tau, and α-synuclein, for example, contributing to Alzheimer's, Parkinson's, and other neurodegenerative conditions. Meanwhile in the rest of the body, transthyretin amyloid is likely important in heart failure, while a number of other types of amyloid (such as medin) likely contribute to aging in more subtle ways.

Our biochemistry is capable of clearing protein aggregates via a form of autophagy called aggrephagy. Autophagy is the name given to a collection of processes that identify and flag unwanted molecules and structures, and in a variety of ways deliver those flagged molecules and structures into a lysosome. Once inside a lysosome, enzymes break down the material for recycling. Clearly the normal operation of aggrephagy is not sufficient to the task of keeping persistent aggregates from accumulating to cause disease, but it does have an impact. Thus the research community is interested in finding ways to meaningfully enhance the operation of aggrephagy. That in turn requires a better understanding of how exactly aggrephagy functions.

Your cells break down protein clumps to smaller pieces before taking it to the trash

A new study shows that our cells' ability to clean out old protein clumps, known as aggregates, also includes a previously unknown partnership with an engine that breaks down bigger pieces into smaller before "taking it to the trash." The process involves something called the proteasomal 19S subunit and DNAJB6-HSP70-HSP110 chaperone module, which together practically form a grinder. This is a very important key that may lead to better treatments of diseases like characterized Alzheimer's, Parkinson's, Huntington's, ALS, and other diseases that are characterized by the accumulation of clumps, in most cases formed by a specific protein

"We know that augmenting autophagy, which is one of the two major cleaning systems in our cells, can delay the onset of several of the devastating neurodegenerative diseases mentioned. Our findings suggest that a combined treatment where we enhance both the breaking down of the big protein clumps into smaller pieces to make them a better substrate for autophagy and autophagy, may be a much better therapeutic approach for these diseases. We are just starting to decipher the mechanism of this whole cell-cleaning process, and we need to deep dive into the details before we can start to work on actual treatments, but understanding how we can enhance it, will certainly help to eliminate, at least partially, those toxic protein aggregates leading to the above-mentioned lethal neurodegenerative diseases."

A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy

Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.

For those of us in the Northern Hemisphere, autumn is underway. The fall is a time when the leaves that are green turn to brown, so let us see what the Lifespan team has been working on to help our field keep our own metaphorical leaves green and healthy.

Top longevity news stories of Summer 2025

As always, we have been bringing you the best longevity and aging research news this summer; let’s take a look at some of the top stories.

Tragedy at RAADFest

Two people nearly died, and several more sought treatment, after receiving peptide injections at the last RAADfest in Las Vegas. This highlighted some well-known problems and contradictions in the longevity field.

On one hand, there is a sense of urgency that pushes some people to offer and others to try therapies that have not been rigorously tested for safety and/or efficacy. Many people rightfully lament the increasingly lengthy and expensive regulatory process, which is not properly suited for rejuvenating therapies. There is a growing push to extend the “right to try” to all patients and all reasonably safe therapies, and to accelerate clinical trials by relaxing certain regulations and transitioning towards cost-effective methods, such as human organoids and in silico models.

On the other hand, a legitimate concern exists that the longevity movement might be overshadowed, compromised, and ultimately impeded by the murky wave of overblown claims, unfounded promises, unproven therapies, and flat-out “snake oil” cures. To make some sense of all this in the context of the RAADfest incident, we asked several prominent figures in the field about this incident and what led up to it.

A vertical longevity village in San Francisco

In the heart of San Francisco, a tower in the downtown area is transforming into a center for longevity, artificial intelligence, cryptocurrency, and robotics.

In March, three young German business owners, Jakob Drzazga, Christian Nagel, and Christian Peters, acquired a 16-story building located in San Francisco’s Mid-Market district. They plan to convert the tower into a premier collaborative workspace for various innovative fields, including cryptocurrency, artificial intelligence, robotics, and longevity research.

Lifespan journalist Arkadi Mazin attended their inaugural longevity conference in June to cover these developments. Join us to find out what he learned at Viva Frontier Tower.

Rejuve.AI: A new app focused on longevity

Rejuve.AI is a company founded by Jasmine Smith and well known AI researcher Ben Goertzel. Recently, they have launched a new longevity app, and Arkadi caught up with them to find out more.

Apparently, it is much more than simply yet another health and lifestyle app. The founders say it focuses on using real human data to study lifespan and potentially the efficacy of inventions that target aging.

In this interview we also discuss Ben and Jasmine’s predictions on the future for artificial intelligence, aging research, and how to create a world where medical data is controlled by patients.

But is this just another app or a longevity research network? Join us as we explore that question in this thought provoking interview.

Longevity in Ireland

The Longevity Summit Dublin has become quite the go-to event in the longevity community. The event first launched in 2022 and has grown in popularity since then.

Dublin is most famous for its Guinness brewery along with the pubs and restaurants of Temple Bar and its long history, but there is a significant buzz about longevity there too.

Hosted at Trinity College in the centre of Dublin, the event is very much in the heart of this vibrant city. The event saw a range of great speakers and workshops focused on aging research and advocacy. It really is great to see the popularity of this event growing and including a free public open day.

Lifespan Editor-in-Chief Steve Hill was at the Summit to bring you the highlights from the 2025 Longevity Summit Dublin. Join us as he shares his thoughts on some of the most interesting news from the conference.

Announcing the Lifespan Alliance

We have also launched the Lifespan Alliance, our corporate sponsorship program that brings together purpose-driven businesses and innovative organizations focused on promoting a longer, healthier human lifespan.

Sponsorship from Alliance members allows us to conduct innovative research, reach millions via news and other media, and link prominent figures in science, policy, and technology to speed up advancements.

If you are interested in supporting us as a company, including the benefits of doing so, please consider becoming a member of the Lifespan Alliance.

We would like to thank all of the organizations that have stepped up to join us so far. Your support means the world to us and allows us to continue our important research, advocacy, journalism, and educational activities.

Organizational leadership changes

There have been some changes to leadership at LRI. Keith Comito and Dr. Oliver Medvedik have become the Chief Executive Officer and Chief Scientific Officer, respectively. They will spearhead LRI leadership and enhance the Institute’s outreach and scientific efforts.

These new roles demonstrate LRI’s dedication to merging innovative leadership with scientific precision and utilizing years of experience in ecosystem development to establish a network that can effectively identify and address key challenges in aging research.

A new lease on life for the Rejuvenation Roadmap

The Rejuvenation Roadmap is a database tracking the many interventions against aging currently being developed and tested. It holds information about each therapy’s progress, from initial drug discovery through to clinical trials. It is a one-stop shop for finding out where the field is in bringing aging under medical control.

With that in mind, we are delighted to announce that Michael Rae is now curating the Rejuvenation Roadmap. Michael is the co-author of the well known rejuvenation biotechnology book Ending Aging, was a science writer for SENS Research Foundation, and is an active member of the longevity community.

We have also added two new aging damage types to the Roadmap: extracellular matrix damage and extracellular aggregates. We have added them to the Roadmap as they are important to our research and more accurately encompass our work.

Extracellular matrix damage involves the degradation and restructuring of its structural and functional elements that make up the extracellular matrix. This is the non-cellular part of tissues that offers structural support and a framework for cells.

Extracellular aggregates refer to a type of defective proteins that have lost their functionality. Instead, they have transformed into adhesive, misshapen forms that adhere to the surfaces of our cells and tissues, disrupting their proper functioning.

Michael has already been busy updating the Roadmap with new drugs and interventions. Keep your eyes out for more in the coming months as the database continues to grow.

A new look for our website

You may have noticed our website has changed a bit recently. Our regulars will recall that LEAF and SRF merged in October 2024 to create the Lifespan Research Foundation (LRI). It has taken a while, but we have now merged both org websites into one.

We like to think of our new site as a longevity switchboard, a place to connect with all of our initiatives. You can find the latest news about the field, learn about our exciting research projects at our Mountain View research centre, check out our educational programs, join the Longevity Investor Network, and much more!

Our goal is simple. Everything you need to know about rejuvenation biotechnology in one place. For those of you who visit us for the latest longevity news, please bookmark the news landing page.

Talking cellular senescence at Longevity Summit Dublin

At the 2025 Longevity Summit Dublin in June, Dr. Amit Sharma gave a talk about some of the work happening at our research center. Our Sharma Lab in Mountain View, California is conducting important research on senescent cells and therapeutic approaches to removing them.

Normally, cells becoming senescent is a helpful safety mechanism that helps us to avoid cancer. Damaged and worn-out cells pose a risk and need to be destroyed via a self-destruct process known as apoptosis.

The problem is that as we age, this safety system breaks down and cells that should be removed no longer are. They instead resist apoptosis and remain at large in the body, causing chronic inflammation. The accumulation of excessive numbers of senescent cells is one of the hallmarks of aging.

It has also been determined to affect the other reasons we age. This diagram shows how it affects other age-related damages. Senescent cells appear twice in the image because they can also encourage other nearby healthy cells to become senescent as well. This is caused by the inflammatory secretions known as the senescence-associated secretory phenotype (SASP).

Senescent cell accumulation is linked to a wide variety of age-related diseases:

• Cognitive decline
• Frailty
• Type 2 Diabetes
• Obesity-induced dysfunction
• Atherosclerosis
• Non-alcoholic fatty liver disease (NAFLD)
• Alzheimer’s disease
• Parkinson’s disease
• Idiopathic Pulmonary Fibrosis (IPF)
• Chronic obstructive pulmonary disease (COPD)
• Liver fibrosis
• Osteoarthritis
• Osteoporosis
• Age-related muscle loss (sarcopenia)
• Heart failure
• Hypertension
• Therapy-induced senescence (TIS)
• Rheumatoid arthritis
• Kidney disease (Glomerulosclerosis)
• Macular degeneration
• Chemotherapy-induced fatigue

The research we are doing at the Sharma Lab aims to tackle such diseases by targeting senescent cells. Potentially, this means that therapies based on our research might address many diseases of aging by attacking a core reason that they develop in the first place. Here’s some of the research we are doing at our Mountain View research center.

Iron dyshomeostasis and ferroptosis-based senolytics

Most studies on senescent cells have focused on primary senescent cells. These are the classic senescent cells that become this way due to DNA damage, replicative exhaustion, or mitochondrial dysfunction.

However, more recently, researchers have discovered what are known as paracrine senescent cells, which become senescent due to prolonged exposure to the SASP. This creates a vicious cycle where more and more cells become senescent due to SASP exposure.

Paracrine senescent cells play a key role in the buildup of senescent cells as we age. Previous attempts to define paracrine senescence have been inconsistent because they relied on analyzing mixed groups of both senescent and non-senescent cells.

Dr. Sharma and his team found that senescent cells accumulate iron but resist ferroptosis. This is a type of cell death that is accompanied by a large amount of iron accumulation and lipid peroxidation.

Senescent cells are not destroyed by accumulated iron like healthy cells are. They survive by repairing the plasma membrane and reducing the lipid peroxides induced by iron accumulation. These lipid peroxides create reactive oxygen species (ROS), which the senescent cells actively remove in order to survive.

With this in mind, the team used dipeptidyl peptidase-4 (DPP4) as a surface maker to isolate senescent cells from regular cells. Our researchers found that ferroptosis dysregulation and ferrous iron accumulation are a common phenomenon in both primary and paracrine senescent cells.

Finally, our researchers identified drugs capable of inducing ferroptosis in target senescent cells. Essentially, the cells were already primed for ferroptosis cell death but were resisting it, and these drugs effectively tipped them over the edge. The approach works in primary and paracrine senescent cells.

These results have given us important insights into the nature of senescent cell populations and how we might approach their identification and clearance in a new way.

LAMP1 is a universal surface marker of senescence

Researchers at LRI have identified a cell surface marker of senescence that could make identifying senescent cell populations more reliable.

There have been many attempts to create accurate biomarkers in order to identify senescent cell populations. While there are some methods to do so, these have limitations and are less than adequate. It is therefore very important for reliable senescent cell biomarkers to be identified, otherwise it is impossible to confirm if an intervention is effective.

Senescent cells have increased lysosomal function. Lysosomes are bubble-shaped organelles that engulfs cellular waste and removes it from the cell. It does this by merging with the outer membrane to eject the waste through a process known as lysosomal exocytosis.

Researchers at LRI have used a database of membrane proteins to identify a protein called LAMP1. This protein is only present in healthy cells for a short time during lysosomal exocytosis, but in senescent cells, it persists.

Dr. Sharma and his team found a correlation between the expression of LAMP1 and senescence associated genes, including p21 and p16. They tested this association in human fibroblasts in a number of ways and found that LAMP1 expression increased significantly in senescent cells.

Untreated cells only expressed LAMP1 around 1% of the time, while cells that had induced senescence saw expression 20-60% of the time. How much depended on how senescence was induced in the cells.

We then investigated the possibility of utilizing LAMP1 as a therapeutic target. The team used an antibody-drug conjugate (ADC), which is comprised of an antibody aimed at a particular cell surface protein. The ADC was used to target LAMP1, which caused the senescent cells to die but didn’t affect healthy cells.

Ultimately, this opens up the possibility that LAMP1 could be a target for senolytic therapies that help clear harmful senescent cells. These are just two examples of how LRI is making important advances and driving progress in the aging research field.

Rejuvenation biotechnology has an advocacy problem

Advocacy is one of the most important things in our field, yet it is often the most overlooked thing. Often, the focus is understandably on the research side of things, but this comes at the cost of effectively engaging with policymakers, the medical world, and the public. While doing the actual research and achieving breakthroughs is critical, we also need to combine this with effective advocacy and communication strategies.

For years, we have watched the field develop, and one thing that has always struck us is how different groups in our community are often at odds with each other when it comes to advocacy. This has often led to completely opposing strategies, a disorganized community, and an unclear message. This is obviously not ideal.

Some groups suggest that public engagement isn’t important at all and that the focus should be on the science until there is something to show. Other groups believe that we should be engaging the public to pave the way for the emerging technologies that are to arrive. At face value, both of these seem like reasonable positions to take.

There may be a middle ground between both approaches, but how would we know, and how can we better understand public sentiment?

Developing a cultural intelligence platform for advocacy

This is why we are supporting the development of a cultural intelligence platform by the Public Longevity Group (PLG). Its goal is to create tools to gauge public sentiment, measure the impact of media coverage, study social media activity relating to the field, and develop optimal communication strategies to reach as-yet-untapped audiences.

In this video, Sho, the founder of PLG, highlights the importance of public trust in promoting rejuvenation biotechnology. He emphasizes that mere scientific advancements are insufficient; cultural acceptance and comprehension are vital. PLG employs data-driven techniques to assess public opinion, monitor discussions, and craft engaging narratives that appeal to various demographic groups.

By refining communication strategies and building partnerships with organizations like the Lifespan Research Institute, PLG aims to bridge the gap between science and society, ensuring that advancements are not only scientifically possible but are socially accepted.

Scientific narratives focusing on rejuvenation and longevity are gaining traction, while lifestyle-based messaging is plateauing, suggesting a shift in public interest towards more advanced interventions. Now is the perfect time to develop the tools to optimize our advocacy efforts.

Key points of the project:

• The research is advancing, but for it to have a meaningful impact, gaining public trust, cultural acceptance, and legitimacy are essential. Without these, scientific breakthroughs may fail to reach the public or gain momentum.
• Framing longevity in terms of long-term health and independence can significantly increase public support, shifting attitudes from opposition to acceptance.
• The cultural intelligence platform will use strategic methods like tracking online discourse, conducting high-resolution surveys, and analyzing consumer behavior to understand public sentiment around longevity.
• The cultural intelligence platform will also identify underserved regions and demographics, revealing new opportunities for targeted outreach.
• Data-driven experiments will be used to test which narratives and communication strategies resonate across different demographics and political identities.
• Finding new ways to communicate about the science using fresh metaphors, entry points, and language that engages the public without diluting the mission.
• Recognizing the need for data-driven cultural insights to foster public engagement and collaboration within the rejuvenation and longevity field. This is a group effort, and we need to work together to make things happen.
• PLG is already collaborating with key organizations like the Alliance for Longevity Initiatives and the University of Texas Medical Branch to turn cultural insights into actionable strategies for advancing longevity science.

The cultural intelligence platform campaign is live on the LRI website now; please help us to build the tools our movement needs to succeed! Thank you to everyone who has already stepped up to support this important initiative.

The composition of the gut microbiome changes with age, and researchers have demonstrated that many of these changes correlate with worse outcomes in aging. In animal studies, altering the composition of the gut microbiome to be more youthful produces health benefits, indicating that changes in the gut microbiome contribute to aging, but similar data in humans remains sparse. Mendelian randomization is a way to use genetic differences across a study population to infer whether or not a given correlation indicates causation. The results are not conclusive, but add support for causation to the be the case. Here, researchers mine a large database of gut microbiome composition, genetics, and health outcomes in an attempt to find specific cases in which an aspect of the gut microbiome, such as increased numbers of a given microbial species or altered production of a specific metabolite, is a contributing cause of an aspect of degenerative aging.

In the past 20 years, the involvement of gut microbiome in human health has received particular attention, but its contribution to age-related diseases remains unclear. To address this, we performed a comprehensive two-sample Mendelian Randomization investigation, testing 55,130 potential causal relationships between 37 traits representing gut microbiome composition and function and age-related phenotypes, including 1,472 inflammatory and cardiometabolic circulating plasma proteins from UK Biobank Pharma Proteomic Project and 18 complex traits.

A total of 91 causal relationships remained significant after multiple testing correction and sensitivity analyses, notably two with the risk of developing age-related macular degeneration and 89 with plasma proteins. The link between purine nucleotides degradation II aerobic pathway and apolipoprotein M was further replicated using independent genome-wide association study data. Finally, by taking advantage of previously reported biological function of Faecalibacterium prausnitzii we found evidence of regulation of six proteins by its function as mucosal-A antigen utilization.

These results support the role of gut microbiome as modulator of the inflammatory and cardiometabolic circuits, that may contribute to the onset of age-related diseases, albeit future studies are needed to investigate the underlying biological mechanisms.

Link: https://doi.org/10.18632/aging.206293

The innate immune cells known as macrophages adopt different packages of behaviors (known as polarizations) depending on circumstances. Most research is focused on the difference between the pro-inflammatory M1 polarization and the anti-inflammatory M2 polarization. M2 is considered to be more regenerative, and many issues in aging are thought to involve the presence of too many M1 macrophages. Yet M1 macrophages do play a role in regeneration, as noted here, and this contribution is also disrupted with age to inhibit the ability to regrow muscle in older individuals. This is one of the aspects of macrophage behavior that illustrates the limitations of the simple M1/M2 model; the underlying reality is more of a spectrum of behaviors, and one M1-like macrophage is not necessarily undertaking the same tasks as another.

Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. The essential role of pro-inflammatory macrophages during tissue remodeling are well appreciated given that they are early responders to facilitate the clearance of tissue debris and initiate intracellular communication such as stimulation of satellite cell proliferation and regulation of the deleterious accumulation of collagen and intramuscular adipose from fibroblasts and fibro-adipogenic progenitors.

Macrophage phenotype is metabolically controlled through citric acid cycle intermediate accumulation and activation of hypoxia-inducible factor 1-alpha (HIF1A). We hypothesized that transient hypoxia following disuse in old mice would enhance macrophage metabolic inflammatory function thereby improving muscle cellular remodeling and recovery. Old (20 months) and young adult mice (4 months) were exposed to acute (24h) normobaric hypoxia immediately following 14-days of hindlimb unloading and assessed during early re-ambulation (4- and 7-days) compared to age-matched controls.

Treated aged mice had improved pro-inflammatory macrophage profiles, muscle cellular remodeling, and functional muscle recovery to the levels of young control mice. Likewise, young adult mice had enhanced muscle remodeling and functional recovery when treated with acute hypoxia. Treatment in aged mice restored the muscle molecular fingerprint and biochemical spectral patterns (Raman Spectroscopy) observed in young mice and strongly correlated to improved collagen remodeling. Finally, intramuscular delivery of hypoxia-treated macrophages recapitulated the muscle remodeling and recovery effects of whole-body hypoxic exposure in old mice. These results emphasize the role of pro-inflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.

Link: https://doi.org/10.1172/jci.insight.194303