LongeCityNews Last Updated: 28 March 2026 - 04:08 PM

Lipid metabolism is a complex area of study. Any given lipid can be transformed into scores of other molecules with quite different properties, and the scientific community's understanding of what each of these lipid products is doing in our biology is far from complete. Even just looking at cholesterol alone quickly becomes a sizable undertaking; if you were under the impression that researchers know exactly what every modified form of cholesterol or transformed product of cholesterol does in detail, you may be surprised to see just how much is left to catalog, map, and comprehend. Cellular biochemistry is very complicated, and there are only so many researchers and only so much time.

So science tends to proceed by establishing points of focus on specific molecules or specific interactions, and incrementally mapping nearby molecules and interactions. The further away from these points of focus one moves, the less complete the understanding. One of the scientific programs first started in the SENS Research Foundation has led to a growing point of focus on 7-ketocholesterol and its effects. 7-ketocholesterol is a oxidized form of cholesterol known to be toxic and thought to have no useful purpose in metabolism. Evidence points to a role for 7-ketocholesterol in atherosclerosis and a range of other conditions, and thus a company, Cyclarity Therapeutics, was formed to develop therapies to clear 7-ketocholesterol from tissues. That program is currently in its early clinical stages.

The scientific process doesn't stop at "7-ketocholesterol is toxic, and thus we should clear it from tissues to improve health", however. 7-ketocholesterol exists in the sizable space of alterations to cholesterol and products of cholesterol. Many of the transformations that can be applied to cholesterol can also be applied to 7-ketocholesterol. Do researchers have a good idea as to what these further derivatives of 7-ketocholesterol are doing to cells? Not really, but the point of focus established on 7-ketocholesterol will expand slowly to these products and their effects.

Emerging role of 7-Ketocholesterol and hydroxylated 7-Ketocholesterol in the pathophysiology of disease

Cholesterol is a vital lipid molecule essential for cellular structure and function. Oxidation of cholesterol leads to the formation of biologically active oxidized cholesterols known as oxysterols. Among oxysterols, 7-ketocholesterol (7KC) is a key product, primarily formed by oxidation at the C7 position of the cholesterol molecule. 7KC is notably elevated in conditions such as hypercholesterolemia and within atherosclerotic lesions, often at higher concentrations than other oxysterols. Growing research highlights 7KC's significant involvement in the development and progression of a wide array of diseases and aging cells, where it is widely recognized for its cytotoxic, pro-inflammatory, and pro-apoptotic properties, positioning it as a critical factor in pathophysiology.

While 7KC has traditionally been studied as an end-product of cholesterol oxidation, increasing evidence suggests that it also serves as a precursor or co-product in the generation of more structurally complex oxysterols bearing multiple oxidative modifications. Among these, double-substituted oxysterols such as 7-keto-25-hydroxycholesterol (7-keto-25-OHC) and 7-keto-27-hydroxycholesterol (7-keto-27-OHC) represent an underexplored but potentially significant class of downstream metabolites.

The presence of both a C7 ketone and a side-chain hydroxyl group profoundly alters sterol polarity, membrane partitioning, and reactivity. Compared with mono-substituted oxysterols, double-substituted species are expected to exhibit reduced membrane affinity, enhanced aqueous solubility, and increased accessibility to intracellular targets. These physicochemical properties may influence their transport, cellular distribution, and rate of further metabolism or clearance. Moreover, the coexistence of two oxidative modifications may amplify biological activity, either through additive effects or through the emergence of distinct signaling properties not observed with single modifications. These metabolites of 7KC represent the dynamic interplay between oxidative damage and cellular sterol metabolic pathways. Elucidating their biological functions will be essential for a more comprehensive understanding of oxysterol biology in health and disease.

Rubedo Life Sciences, Inc. (Rubedo), an AI-driven, clinical-stage biotech focused on discovering and rapidly developing selective cellular rejuvenation medicines targeting aging cells, today announced preliminary results from a single-center, ascending-dose, randomized, double-blind, vehicle-controlled trial in patients with plaque psoriasis, atopic dermatitis, and skin aging (photo-aged skin). The recently completed Phase 1 clinical trial, conducted in the European Union, was designed to assess the safety, tolerability, clinical effects, plasma bioavailability, and pharmacodynamics of topical RLS-1496—the first-ever GPX4 (selective glutathione peroxidase 4) modulator to be studied in human trials, and the first specifically targeting cellular rejuvenation, an area of great interest to the scientific community as a new therapeutic pathway. The study met its primary endpoint, with RLS-1496 also demonstrating early signs of efficacy.

“We are excited by the potential of this treatment with the clinical and biomarker changes we have observed already.” – Rubedo CEO Frederick Beddingfield, III, MD, PhD, FAAD.

Preliminary Trial Results

• RLS-1496 was well-tolerated, with no serious adverse events (AEs) and no discontinuations due to AEs or tolerability issues during the 4-week study
• In psoriasis patients:
  • Clear dose-response seen during the trial (0.1%, 0.5%, and 1.0%); all doses were well-tolerated so only 1.0% dose will be evaluated moving forward
  • Dose-related target engagement of RLS-1496 and GPX4
  • Overall reduction in senescent cells seen with RLS-1496 in the mid- and high-dose cohorts
  • Some subjects treated with RLS-1496 had a reduction of senescent cells, which was associated with a reduction of inflammatory cytokines such as IL-19 and S100A7; this reduction was not seen in the vehicle cohort
  • An average 20% reduction in epidermal thickness was observed on histology in subjects treated with RLS-1496 for one month
  • A statistically significant relationship was seen between target engagement and improvement in clinical psoriasis severity
• In atopic dermatitis patients:
  • Even higher levels of target engagement and substantial clinical improvement were seen in atopic dermatitis subjects on RLS-1496
  • After one month of treatment, 25% of subjects on RLS-1496 had a >/=4-point change in pruritus (or itching) on the numeric rating scale (NRS); no vehicle subjects had a 4-point or more change on the NRS
• Early photo-aging data show:
  • Dose-dependent target engagement in non-lesional photo-aged skin
  • Histology, proteomics, and spatial transcriptomics indicate that collagen gene and protein expression increase with treatments over time, in particular, spatial transcriptomics shows an effect in dermal fibroblasts
  • Spatial transcriptomics show indication that SASPs and inflammatory biomarkers decrease with treatments over time in keratinocytes

“We’re pleased by the positive safety and tolerability seen in the trial, with the additional preliminary results exceeding our expectations by showing very promising and clinically meaningful results across multiple measures including histologic, cellular, biomarker, and clinical evaluations in psoriasis, atopic dermatitis, and photo-aged skin,” said Rubedo CEO Frederick Beddingfield, III, MD, PhD, FAAD. “It’s uncommon to see clinical effect in a Phase 1 dermatology study given the shorter study duration and smaller sample size, and we are excited by the potential of this treatment with the clinical and biomarker changes we have observed already.”

Dr. Beddingfield will preview these results during a panel he will moderate on senescence and skin at the Dermatology Innovation Forum (DIF) during the American Academy of Dermatology annual meeting on Thursday, March 26, at 1:05 pm MT in Denver. Additional results from this trial will be presented during an oral presentation at the Society for Investigative Dermatology (SID) from May 13-16, 2026, in Chicago.

A second study for RLS-1496 – a Phase 1b/2a study in actinic keratosis (precancerous skin lesions) – is underway in the United States with completion expected later this year. In both trials, all subjects have their photo-aged skin treated with RLS-1496 in addition to their lesional skin relating to their medical condition. From these trials, Rubedo expects to obtain a large dataset on the treatment of aging skin from approximately 70 subjects.

Rubedo Chief Scientific Officer and Founder Marco Quarta, PhD, said, “This is one of the first comprehensively evaluated trials of a senotherapeutic drug that targets aging pathologic cells and regenerates healthy cells, and also the first human trial of a GPX4 modulator. These preliminary results show the drug working mechanistically as expected and even better than should be expected clinically in a 4-week trial. We are excited for the upcoming comprehensive results from this trial, as well as the results of the ongoing trial in actinic keratosis.”

About RLS-1496 and GPX4 Modulation

Rubedo’s lead candidate RLS-1496, being developed for topical and oral administration, is a potential first-in-class, disease-modifying GPX4 modulator selectively targeting pathologic senescent or “aged” cells that drive chronic degenerative diseases and conditions associated with biological aging processes. These include immunology and inflammation (I&I), dermatology and skin aging, metabolic syndrome (obesity, diabetes, liver fibrosis), sarcopenia, and neurodegenerative disease.

In certain pathologic cells, aging is associated with an imbalance in GPX4. Modulation of GPX4 sensitizes cells to ferroptosis, which is a type of programmed cell death and is believed to be an Achilles heel of senescent cells. By modulating GPX4 in ferroptosis-sensitive senescent “aged” cells, RLS-1496 may be able to clear these cells to not only fight disease, but also support healthy cells to function properly and restore tissue homeostasis. Beyond its targeted senolytic function in triggering selective ferroptosis within pathological senescent cells, RLS-1496 could also act as a restorative modulator that induces a vital ‘redox-reset’ in stressed neighboring cells, effectively clearing the source of chronic inflammation while actively re-establishing healthy tissue homeostasis.

RLS-1496 uses Rubedo’s proprietary, AI-driven drug discovery platform ALEMBIC™, which identifies targets within pathologic senescent cells and develops selective cellular rejuvenation medicines for these targets.

About Rubedo Life Sciences

Rubedo Life Sciences is a clinical-stage biotech developing a broad portfolio of innovative selective cellular rejuvenation medicines targeting aging cells that drive chronic age-related diseases. Our proprietary AI-driven ALEMBIC™ drug discovery platform is developing novel first-in-class small molecules to selectively target pathologic and senescent cells, which play a key role in the progression of pulmonary, dermatological, oncological, neurodegenerative, fibrotic, and other chronic disorders. Our lead drug candidate – RLS-1496, a potential first-in-class disease-modifying GPX4 modulator – is currently in Phase I clinical trials. The Rubedo leadership team is composed of industry leaders and early pioneers in chemistry, AI technology, longevity science, and life sciences, with expertise in drug development and commercialization from both large pharmaceutical and leading biotechnology companies. The company is headquartered in Mountain View, CA, USA, and has offices in Milan, Italy. For additional information, visit www.rubedolife.com.

Scientists used red blood cells as membrane donors to encapsulate healthy mitochondria and send them into diseased cells, achieving improvements across multiple models and conditions [1].

The delivery problem

Mitochondrial diseases are a diverse group of disorders that arise when mitochondria malfunction. They are often caused by mutations in mitochondrial DNA (mtDNA) itself or in nuclear genes encoding mitochondria-related proteins.

Mitochondrial dysfunction is also considered one of the hallmarks of aging – no wonder, given that mitochondria are the main source of energy for most cellular processes. When mitochondria falter due to accumulating mutations or persistent damage, such as oxidative stress, no tissue or organ is safe. Parkinson’s disease is a prominent example of a neurodegenerative disease in which mitochondrial dysfunction plays a central role [2].

If only we could deliver healthy, functional mitochondria into diseased cells! However, researchers pursuing this enticing idea have encountered multiple hurdles. Physical approaches like optical tweezers or photothermal nanoblades can transfer mitochondria with precision, but only into a tiny number of cells, while simply injecting free-floating mitochondria into the bloodstream has produced only modest effects [3].

Success in a dish

In this new study published in Cell, a group of Chinese scientists attempted to solve this problem by encapsulating healthy mitochondria in cellular membranes taken from red blood cells (erythrocytes), hoping that this would protect mitochondria while in the bloodstream and facilitate their uptake by recipient cells. Conveniently, erythrocytes are just plasma membranes with no other organelles inside, which makes them an ideal and clinically safe source of membrane material.

Mitochondria were isolated from donor cells, mixed with erythrocyte plasma membranes from mice or humans, and allowed to self-assemble into capsule-like structures. Mitochondria inside the capsules showed two improved markers of mitochondrial function, higher membrane potential and higher ATP levels, than free mitochondria, suggesting the packaging actually preserves or enhances mitochondrial health.

Capsules containing fluorescently labeled donor mitochondria were then incubated with acceptor cells. Time-lapse videos showed donor mitochondria entering cells through membrane fusion. By 48 hours, donor mitochondria fused with the cell’s endogenous mitochondrial network, with about 80% of acceptor cells acquiring donor mitochondria.

Transplanted mitochondria maintained normal membrane potential, and donor mtDNA reached 71% of the total mtDNA pool. Critically, capsule-mediated delivery was dramatically more efficient than delivering free mitochondria.

In the next experiment, rho zero (ρ0) cells, which have been deliberately depleted of all their mtDNA, were treated. These cells can survive in supplemented culture, but they have severely impaired mitochondrial function.

Donor mitochondria entered ρ0 cells in large numbers, and mitochondrial morphology recovered from swollen (a sign of dysfunction) to normal tubular forms. MtDNA levels were restored to near-normal and persisted for at least 21 days. mtDNA-encoded transcripts and proteins were detected, confirming the DNA was being read and translated.

Next, the researchers treated GM04516 cells – human fibroblasts with a large fragment deletion in mtDNA – with capsules loaded with mitochondria from normal human fibroblasts. 86% of patient cells acquired donor mitochondria. The proportion of mtDNA carrying the deletion fell from 14.4% to 2.67%, while oxygen consumption, ATP production, and cell viability increased.

The team then treated human fibroblasts harboring m.3243A>G, the most common pathogenic mtDNA point mutation, which causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and a range of other syndromes. The mutation rate fell from 92.6% to 73.3%, while mitochondrial protein levels increased. The reduction was smaller than in the deletion model, but cells usually tolerate mitochondrial dysfunction until the fraction of mutant mtDNA exceeds a critical threshold (typically 60-90%, depending on the mutation and cell type).

Improvements in Leigh and Parkinson’s models

The researchers then moved to in vivo experiments, injecting mitochondrial capsules into mice via different routes: intramuscular injection, direct injection into the substantia nigra (a region of the brain important for movement control), and intravenous injection. They also performed intramuscular injection in two cynomolgus monkeys.

After intramuscular injection, transplanted mitochondria were detected in surrounding muscle tissue, after direct brain injection, they were found in both the substantia nigra and cortex, and after IV injection, donor mitochondria were distributed systemically. In cynomolgus monkeys, mitochondria were successfully delivered to muscle tissue.

Next came the turn of mice with a severe Leigh syndrome phenotype. In humans, it is a rare and fatal inherited mitochondrial disorder, usually appearing in infancy and resulting in death within few years. Median survival increased from 48.5 days (untreated) to 61 days (free mitochondria) to 74 days with mitochondrial capsules – impressive in a model with a severe, fully penetrant phenotype.

The big test was a mouse model of Parkinson’s disease. The animals received a toxin that caused mitochondrial dysfunction and cell death specifically in dopaminergic neurons, and then IV injections of mitochondrial capsules twice weekly for one month. The number of functioning dopaminergic neurons was significantly rescued by the treatment. Behavioral testing showed substantial reversal of bradykinesia, the slow movement that is characteristic of Parkinson’s.

The researchers confirmed improvement of mitochondrial function. The effects persisted for at least three months after treatment – the timeframe of the experiment. Free mitochondria failed to produce comparable effects at the same dose and schedule.

Finally, rather than systemic IV injection, the authors injected mitochondrial capsules directly into the substantia nigra. A single intracerebral injection produced a high local abundance of transplanted mitochondria in both the substantia nigra and cortex, significant neuron recovery, and improvements in motor behavior and mitochondrial function. This shows that targeted delivery can achieve therapeutic effects with a minimal number of doses, and that the IV results did not come from a systemic (such as anti-inflammatory) effect.

Literature

[1] Du, S., Long, Q., Zhou, Y., Fu, J., Wu, H., Yang, L., … & Liu, X. (2026). Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson’s disease models. Cell.

[2] Schapira, A. H. V., Cooper, J. M., Dexter, D., Clark, J. B., Jenner, P., & Marsden, C. D. (1990). Mitochondrial complex I deficiency in Parkinson’s disease. Journal of neurochemistry, 54(3), 823-827.

[3] Nakai, R., Varnum, S., Field, R. L., Shi, H., Giwa, R., Jia, W., … & Brestoff, J. R. (2024). Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome. Nature metabolism, 6(10), 1886-1896.

In recent years, researchers have noted that circular RNAs accumulate in cells in old age. It has been unclear as to whether this is only a marker of dysfunction or a change that in and of itself causes further downstream issues. The fastest way to obtain an answer to this sort of question is to repair the problem and see what happens. Researchers here identify that levels of RNASEK, a protein responsible for breaking down circular RNA, decline with age, allowing circular RNA levels to rise. Forcing increased expression of RNASEK slows aging and extends life, which strongly suggests that circular RNAs are harmful in some way. The researchers suggest that harms result from circular RNA aggregation in the cell, but further research is needed on this topic.

Until now, circular RNA has been regarded mainly as an aging marker because of its stability, which allows it to accumulate over time. However, the molecular mechanism for removing this RNA and its direct link to aging had not been clearly identified. Using Caenorhabditis elegans, a short-lived roundworm widely used in aging research, researchers first confirmed that the circular RNA-degrading enzyme RNASEK is essential for longevity. They also discovered that as aging progresses, the amount of RNASEK decreases, resulting in an abnormal accumulation of circular RNA within cells.

Conversely, artificially increasing the levels of RNASEK (overexpression) extended the lifespan and allowed the organisms to survive longer in a healthy state. This implies that the process of appropriately removing cellular circular RNA is critical for maintaining health and longevity.

The research team also found that RNASEK prevents the toxic aggregation of circular RNAs in aged organisms. When RNASEK is deficient and circular RNA accumulates, "stress granules" form abnormally inside the cell, which can impair cellular functions and accelerate aging. RNASEK works alongside the chaperone protein HSP90 (which helps proteins avoid misfolding or clumping) to inhibit the formation of these stress granules and help cells maintain a normal state. Notably, this phenomenon was observed not only in C. elegans but also in human cells. In mammals, RNASEK also functions to directly degrade circular RNA; a deficiency of RNASEK in human cells and mouse models led to premature aging.

Link: https://news.kaist.ac.kr/newsen/html/news/?mode=V&mng_no=59490