Mitochondrial DNA is highly prone to mutation due to a variety of factors and these mutations result in several pathologies. Our endeavor is in identifying gene therapy approaches to address these mutations. The COX2 gene is a core component of Complex IV in the oxidative phosphorylation relay. Mutations in this gene are associated with Complex IV deficiency affecting a critical step in the oxidation of cytochrome C using molecular oxygen.

Our lab has successfully produced proteins for all 13 genes found in mitochondria by allotopic expression, but only one (ATP8) has successfully restored function in a disease-model cell line. Natural evolution has already transferred more than 1000 genes from mitochondrial DNA to the nucleus. Our goal is to find variants of the COX2 gene that can help cells function properly by mimicking the natural evolutionary process. Results from such an experiment would not only be a significant step towards efficacious COX2 gene therapy but would also provide key insights into the genetic changes necessary for successful allotopic expression of all mitochondrial genes.

We propose to generate more than 1 million variants for the COX2 gene using error-prone PCR similar to a study performed in yeasts and test these variants in rescuing oxidative phosphorylation, a function that is crucial for ATP production in cells. The nutrients that we consume are metabolized to CO2 and high-energy electron donors that further combine with oxygen to convert ADP to ATP. We will test this in a human model cell line that is lacking the COX2 protein. This cell line is unable to grow in nutrient medium restrictive for oxidative phosphorylation. Upon placing the variants in such a medium, only cells that are capable of performing oxidative phosphorylation can survive. Such a screen would allow us to identify functional variants of the COX2 gene for further analysis.

Previously, researchers developed a vaccine to eliminate senescent cells expressing senescence-associated glycoprotein (SAGP) - a senolytic vaccine that improved various age-related diseases including atherosclerosis and type 2 diabetes in mice. Another study also found that SAGPs are highly expressed in glial cells in people with Alzheimer's disease. Based on the findings from these studies, the researchers tested this vaccine in mice to target SAGP-overexpressed cells to treat Alzheimer's disease.

In this study, the research team created an Alzheimer's disease mouse model that mimics a human brain and simulates amyloid-beta-induced Alzheimer's disease pathology. To test the efficacy of the SAGP vaccine, the mice were treated with a control vaccine or the SAGP vaccine at two and four months old. Usually, people in later stages of Alzheimer's lack anxiety, which means they are not aware of the things around them. The mice who received the vaccine had anxiety, which means that they were more cautious and more aware of things around them - a sign researcher say could indicate a lessening of the disease. In addition, several inflammatory biomarkers of Alzheimer's disease were also reduced.

The SAGP vaccine significantly reduced amyloid deposits in brain tissue located in the cerebral cortex region, which is responsible for language processing, attention and problem solving. The astrocyte cell (the most abundant type of glial cell in the brain and a specific inflammatory molecule) was shown to be decreased in size in mice receiving the vaccine. A reduction in other inflammatory biomarkers was also seen, implying that inflammation in the brain improved in response to the SAGP vaccine. A behavior test on the mice at six months old revealed that those that received the SAGP vaccine responded significantly better to their environment than those who received the placebo vaccine. The SAGP-vaccinated mice tended to behave like normal healthy mice and exhibited more awareness of their surroundings.

The SAGP protein was shown to be located very near to specialized brain cells called microglia, which play a role in the immune defense of the central nervous system. Microglia help clear damaging plaque formed by proteins; however, they also trigger brain inflammation that can damage neurons and worsen cognitive decline in a person, which could be one of the causes of Alzheimer's disease development.

How long can human beings live? Although life expectancy has increased significantly over the past century, thanks largely to improved sanitation and medicine, research into hunter-gatherer populations suggests that individuals who escaped disease and violent deaths could live to about their seventh or eighth decade. This means our typical human life span may be static: around 70 years, with an extra decade or so for advanced medical care and cautious behavior. Some geneticists believe a hard limit of of around 115 years is essentially programmed into our genome by evolution.

Other scientists in the fast-moving field of aging research, or geroscience, think we can live much longer. A handful of compounds have been shown to lengthen the life spans of laboratory animals slightly, yet some scientists are more ambitious - a lot more ambitious. João Pedro de Magalhães, a professor of molecular biogerontology at the Institute of Inflammation and Ageing at the University of Birmingham in England, thinks humans could live for 1,000 years. He has scrutinized the genomes of very long-lived animals such as the bowhead whale (which can reach 200 years) and the naked mole rat. His surprising conclusion: if we eliminated aging at the cellular level, humans could live for a millennium - and potentially as long as 20,000 years.

"I actually did some calculations years ago and found that if we could "cure" human aging, average human life span would be more than 1,000 years. Maximum life span, barring accidents and violent death, could be as long as 20,000 years. This may sound like a lot, but some species can already live hundreds of years-and in some cases thousands of years [such as the hexactinellid sponge and the Great Basin bristlecone pine]. If we could redesign our biology to eliminate cancer and evade the detrimental actions of our genetic software program, the health benefits would be mind-boggling. I think it's possible. Is it going to happen soon? I think it's quite unlikely. Even if you can figure out how aging works, it is not easy to develop interventions."

In this study, we designed a fast and efficient genome-wide screening assay in C. elegans to systematically identify potential regulators of motor aging. Among the top hits, we functionally validated the role of VPS-34 in regulating motor aging and revealed its cell type-specific mechanisms. VPS-34 is the class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI(3)P), regulating motor function in aged but not young worms.

Contrary to popular belief that life span and health span are strongly correlated, the global increase of life expectancy over the past decades is rarely accompanied by increased health span. Since aging is characterized by functional decline of multiple organs and tissues, the key to healthy aging is to delay or rescue the decline of essential physiological functions. Motor independence is strongly associated with the quality of life of elderly people, yet motor aging is a common, conserved biological process from worms to humans, leading to frailty, loss of motor independence, falling, and even death. To date, it is still challenging to identify evolutionarily conserved mechanisms that can be exploited to delay or ameliorate motor aging.

Combining genetics, pharmacology, and in situ electrophysiology, we demonstrated that partial inhibition of VPS-34 significantly improved both neuromuscular synaptic transmission and muscle integrity, which ameliorate motor aging in both worms and mice. Previous studies have identified motor aging-associated regulators through candidate approaches, which act in either motor neurons/neuromuscular junctions or skeletal muscles. To our knowledge, VPS34 is the first reported gene that simultaneously regulates neurotransmission of motor neurons and muscle integrity during aging, likely through cell type-specific mechanisms. Thus, it is a promising target that can be exploited to improve both aged neurons and muscle.

Given the importance of senescence in physiological processes, it is reasonable to think that there is a threshold beyond which the accumulation of senescent cells induces a microenvironment conducive to the development of pathologies via SASP. The accumulation of senescent cells can also occur when the immune system ages, altering the ability of immune cells to clear senescent cells. Elimination of senescent cells by senolytics demonstrated a contributive role of senescent cells in ageing and age-related diseases and paved the way for the development of senotherapeutic approaches. Therefore, over the past 5 years, senotherapeutic research has emerged to slow down the ageing phenotypes. Current senotherapeutic strategies targeting senescent cells are mainly based on drugs that specifically kill senescent cells (senolytics) and components that suppress the detrimental effects of SASP without inducing senescent cell death (senomorphics, also known as senostatics).

We will not cover all senotherapeutic strategies, especially as excellent reviews have recently been published on senolytic developments, but rather focus on those with senomorphic activities, based on their ability to block SASP components.

A first strategy would consist in using neutralizing antibodies, recognizing and blocking specific surface proteins upregulated at senescence. Secretion of IL-6 has been decreased in senescent HUVECs and fibroblasts treated with anti-TNFα or anti-ephrin B2 antibodies, respectively. Several other surface proteins are known to play a role in the regulation of SASP profiles, including SCAMP4, Notch, and CD36. However, it has not yet been reported that the use of neutralizing antibodies targeting SCAMP4, Notch, or CD36 can impact the composition of SASP and, therefore, arrive at a conclusion regarding their senomorphic properties. In a model of bleomycin-induced senescence, the secretion of certain SASP factors (including IL-6 and IL-8) can be directly inhibited with neutralizing antibodies such as those against the membrane-bound IL-1α. It would be interesting to investigate the impact of other neutralizing antibodies directed against other major SASP factors such as circulating IL-1β-, IL-6, or their receptors, on their abilities to alter the chemical composition of SASP, impair SASP-mediated effects, and attenuate other features of senescence in different cell types.

A second strategy would be to use pharmacological and natural compounds. Many senomorphics are polyphenols (including flavonoids, phenolic acids and lignans) that possess antioxidant activities, but their modes of action have not been thoroughly studied. Other senomorphics are plant extracts consisting of a mixture of terpenes, alkaloids, and polyphenols. The biological effects of these compounds are multiple, ranging from the activation of antioxidant enzymes to the reduction in interleukin or MMP expression, and the inhibition of MAPKs. Most senomorphics modulate the senescent phenotypes to disrupt the proinflammatory nature of senescent cells.

Most studies, however, have only assessed a few SASP major factors (such as IL-6, IL-1β, and MMPs) following senomorphic treatments, which is not representative of SASP as a whole. Moreover, the impact of senomorphics on the secretion of extracellular matrix components, microvesicles, and complex lipids remains largely unexplored. Senomorphics can act on multiple targets depending on the context, the nature, and the model of senescence. In some cases, we cannot rule out that they might even increase the secretion of some detrimental factors. This raises the concern that SASP resulting from senomorphic treatment should probably be less deleterious and should be considered as modified rather than non-senescent-like. In addition, few studies are using conditioned media from senescent cells treated with senomorphics to examine the biological effects of the modified SASP (such as the pro-tumoral impact or differentiation) on other cell types. In the absence of more extensive data, it is difficult to assess the real effectiveness of senomorphics on SASP.

When a fragrance wafted through the bedrooms of older adults for two hours every night for six months, memories skyrocketed. Participants in this study reaped a 226% increase in cognitive capacity compared to the control group. The project involved men and women aged 60 to 85 without memory impairment. All were given a diffuser and seven cartridges, each containing a single and different natural oil. People in the enriched group received full-strength cartridges. Control group participants were given the oils in tiny amounts. Participants put a different cartridge into their diffuser each evening prior to going to bed, and it activated for two hours as they slept.

People in the enriched group showed a 226% increase in cognitive performance compared to the control group, as measured by a word list test commonly used to evaluate memory. Imaging revealed better integrity in the brain pathway called the left uncinate fasciculus. This pathway, which connects the medial temporal lobe to the decision-making prefrontal cortex, becomes less robust with age. Participants also reported sleeping more soundly.

Scientists have long known that the loss of olfactory capacity, or ability to smell, can predict development of nearly 70 neurological and psychiatric diseases. These include Alzheimer's and other dementias, Parkinson's, schizophrenia, and alcoholism. Evidence is emerging about a link between smell loss due to COVID-19 and ensuing cognitive decrease. Researchers have previously found that exposing people with moderate dementia to up to 40 different odors twice a day over a period of time boosted their memories and language skills, eased depression and improved their olfactory capacities. The team decided to try turning this knowledge into an easy and non-invasive dementia-fighting tool.

A healthy brain requires sufficient supplies of glucose and oxygen to function properly, and any impairment of the vasculature will affect their delivery to the target cells. The brain and cardiovascular system work closely together in a common endeavour to match energy supply to demand. Their intimate relationship is reflected in the concept of the neurovascular unit (NVU), corresponding to consideration of the neurons, astrocytes, microglia, pericytes, endothelial cells, and basement membrane as a single functioning entity.

The risk of neurodegenerative disorders increases with age, due to reduced vascular nutrition and impaired neural function. However, the interactions between cardiovascular dynamics and neural activity, and how these interactions evolve in healthy aging, are not well understood. Here, the interactions are studied by assessment of the phase coherence between spontaneous oscillations in cerebral oxygenation measured by functional near-infrared spectroscopy (fNIRS), the electrical activity of the brain measured by EEG, and cardiovascular functions extracted from ECG and respiration effort, all simultaneously recorded.

Signals measured at rest in 21 younger participants (31.1 ± 6.9 years) and 24 older participants (64.9 ± 6.9 years) were analysed by wavelet transform, wavelet phase coherence, and ridge extraction for frequencies between 0.007 and 4 Hz. Coherence between the neural and oxygenation oscillations at ∼ 0.1 Hz is significantly reduced in the older adults. This reduction in coherence indicates that neurovascular interactions change with age. The approach presented promises a noninvasive means of evaluating the efficiency of the neurovascular unit in aging and disease.

A new study involving over 700,000 U.S. veterans reports that people who adopt eight healthy lifestyle habits by middle age can expect to live substantially longer than those with few or none of these habits. Scientists used data from medical records and questionnaires collected between 2011-2019 from 719,147 people enrolled in the Veterans Affairs Million Veteran Program. The eight habits are: being physically active, being free from opioid addiction, not smoking, managing stress, having a good diet, not regularly binge drinking, having good sleep hygiene, and having positive social relationships.

According to the results, men who have all eight habits at age 40 would be predicted to live an average of 24 years longer than men with none of these habits. For women, having all eight healthy lifestyle factors in middle age was associated with a predicted 21 additional years of life compared to women with none of these habits. Overall, the results showed that low physical activity, opioid use, and smoking had the biggest impact on lifespan; these factors were associated with around a 30-45% higher risk of death during the study period. Stress, binge drinking, poor diet, and poor sleep hygiene were each associated with around a 20% increase in the risk of death, and a lack of positive social relationships was associated with a 5% increased risk of death.

A study that followed thousands of people over 25 years has identified proteins linked to the development of dementia if their levels are unbalanced during middle age. Most of the proteins have functions unrelated to the brain. "We're seeing so much involvement of the peripheral biology decades before the typical onset of dementia." Equipped with blood samples from more than 10,000 participants, researchers questioned whether they could find predictors of dementia years before its onset by looking at a person's proteome - the collection of all the proteins expressed throughout the body. They searched for any signs of dysregulation - when proteins are at levels much higher or lower than normal. The samples were collected as part of an ongoing study that began in 1987. Participants returned for examination six times over three decades, and during this time, around 1 in 5 of them developed dementia.

The researchers found 32 proteins that, if dysregulated in people aged 45 to 60, were strongly associated with an elevated chance of developing dementia in later life. It is unclear how exactly these proteins might be involved in the disease. For example, one of the proteins found with the strongest association with dementia risk - called GDF15 - was not detected in the brain. The study found altered levels of many of the proteins both in the brain tissues of those who had died with Alzheimer's disease, and in the blood of those still living with it. These were associated with the presence of amyloid and tau proteins, which suggests they are somehow involved in processes specific to the disease. Other proteins identified in the study were linked to the immune system, adding to growing evidence for the role of innate and adaptive immune function in dementia.

Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing.

Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration, and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity, and impaired memory capacity.

Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.

Proliferating cell nuclear antigen (PCNA) is an evolutionarily conserved multifaceted protein found in all eukaryotic cells, and it plays a critical role in DNA synthesis and in DNA repair. PCNA forms a ring structure encircling DNA and it acts as a central "hub" to provide an anchorage for the many proteins involved in the replication and repair pathways. The cellular functions of PCNA can be modulated through post-translational modifications on the surface of the protein, altering partner interactions. Historically, PCNA has been widely used as a tumor progression marker.

DNA replication stress is a hallmark of cancer cells. It is used as a major anti-cancer therapeutic strategy by exploiting this cancer-associated feature, through introduction of further DNA damage resulting in catastrophic damage to the cancer cell. Due to its central role in DNA replication and repair, PCNA is a potential target for this anti-cancer strategy. Moreover, the discovery of a distinct isoform of PCNA associated with cancer cells has potentially opened a novel avenue for the development of new chemotherapeutics. Early effects in targeting PCNA have identified several molecules of interest, both small molecule and peptide-based, which have indicated that directly targeting PCNA for cancer therapy may be a viable approach.

We previously described a compound, AOH1160, functioning as a potential inhibitor hit compound of the cancer-associated PCNA isoform (caPCNA), but this compound lacked suitable metabolic properties to proceed further into preclinical/clinical studies. Here, we describe both the detailed molecular characterization of AOH1996, an analog of AOH1160 that exhibits remarkable therapeutic properties: it is orally administrable in a formulation compatible with its clinical use, and in animal studies it almost completely inhibits the growth of xenograft tumors. AOH1996 causes no discernible toxicity at 6 or more times the effective dose in mice and dogs.

Surgical removal of the thymus is recommended in patients with the autoimmune disease myasthenia gravis as a way to halt T-cell-induced immune destruction of nerve endings. For the study, researchers mined data from 1,146 adult patients who had undergone thymus removal, alongside demographically matched control patients who had undergone similar surgeries but kept their thymus. Thymectomy patients had a nearly threefold higher risk of death from a variety of causes, including a twofold higher risk of cancer and a more modest increase in autoimmune diseases.

In an analysis involving all patients with more than five years of follow-up, the rate of death was higher in the thymectomy group than in the general U.S. population ­- 9 percent vs. 5.2 percent, as was death due to cancer, or 2.3 percent vs. 1.5 percent. In a subgroup of patients in whom T-cell production was measured, those who had had their thymus removed had less new production of T-cells, including both helper T-cells and cytotoxic T-cells. Those patients also had higher levels of pro-inflammatory cytokines, which are small signaling proteins associated with autoimmunity and cancer, in their blood.

The analysis was facilitated by recent advances in rapid genetic sequencing of T-cell receptors (TCRs). The technology, called TCR sequencing, has enough resolution to allow scientists to not only identify different types of T cells, but also measure their diversity as a population overall. "This study demonstrates just how vital the thymus is to maintaining adult health."

Loss of proteostasis is a highly conserved feature of aging across model organisms and typically results in the accumulation of insoluble protein aggregates. Protein insolubility is a central feature of major age-related neurodegenerative diseases including Alzheimer's Disease (AD), where hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the established connection between aging and AD risk, therapeutic approaches to date have overlooked aging and proteome-wide protein insolubility as causal factors, instead focusing on Aβ and Tau. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility.

We demonstrate that, in C. elegans, Aβ expression is sufficient to drive proteome-wide protein insolubility. The Aβ-driven insoluble proteome bears a highly significant overlap with the aging-driven insoluble proteome, suggesting there exists a core, sub-proteome which is vulnerable to insolubility. Using human genome-wide association studies (GWAS) we show that this insoluble sub proteome is replete with biological processes implicated across not only neurodegenerative diseases but also across a broad array of chronic, age-related diseases, providing suggestive evidence that age-related loss of proteostasis could play a role in general age-related disease risk.

The different strategies that past companies followed are common answers to the same constraint: there is no regulatory pathway to bring geroprotectors the market. So they either: (a) Develop pre-clinical assets and platform that may have value for other pharmaceutical and biotech companies. (b) Commit to the traditional biotech playbook and treat an age-related disease through a drug that targets a specific pathway or mechanism of aging, collect data to support claims for other indications and expand the label of the medicine over time. (c) Commercialise unproven products (supplements) or experimental treatments (gene therapies) in jurisdictions where the regulatory environments may allow such procedures.

The intrinsic scientific difficulties in translating early stage research into an approved treatment often stood in the way of commercialisation, despite the best efforts of companies and researchers. Some assets got acquired and abandoned and others are still on their path to the clinic. In a perfect world, nobody would forget on the shelf an asset that has the potential to slow down aging. But many factors beyond just the science can influence whether an asset continues along the development pipeline. Even the most promising early research can sometimes fail to translate into an approved product, due to the inherent challenges in drug development.

The company pivots to a different therapeutic area and the asset is no longer core to their strategy. Leadership changes at the company and new decision makers have different priorities, so they discontinue programs started under previous leaders. Patent life expires before the asset has progressed far enough to merit continued investment. Another company develops a similar or superior asset that displaces interest in theirs. The company runs out of funding to progress all assets and must make tough choices about which programs to shelve. Leadership simply loses conviction in the asset's potential for unclear reasons and turns attention elsewhere.

It may be possible to treat an age-related disease by targeting a mechanism of aging and I'm confident some companies will achieve that relatively soon. From an investment and commercial perspective, given the scientific and historical risks, a drug that targets a specific pathway or mechanism of aging to treat a disease has no superior value than any other drug. Unless that drug can slow down aging. But in more than 30 years, despite apparently promising science and significant funding raised, no single longevity biotech startup has succeeded to bring a product to market. Product as in: drug that has been approved by a regulatory agency following thorough clinical trials. So maybe it's time to consider a different strategy: assume the regulatory risk, target aging itself and be preventive instead of curative. Preventive drugs approved for several indications already exist. So bringing to market drugs that slow down the aging process and prevent all age-related diseases is just one step away.

Globally, the lifespan of populations increases but the healthspan is lagging behind. Previous research showed that survival into extreme ages (longevity) clusters in families as illustrated by the increasing lifespan of study participants with each additional long-lived family member. Here we investigate whether the healthspan in such families follows a similar quantitative pattern using three-generational data from two databases, the Leiden Longevity Study (LLS, Netherlands) and the Swedish register data available in the Scanian Economic-Demographic Database (SEDD, Sweden). We study healthspan in 2,143 families containing index persons with 26 follow-up years and two ancestral generations, comprising 17,539 persons.

Studying these long-lived families is important to improve our understanding of the molecular and environmental mechanisms that protect from multimorbidity and promote a healthy survival up to high ages. In this study we showed that members of long-lived families have a delayed onset of disease, multimorbidity, and medication use as compared to their partners, thereby extending their healthspan with up to a decade. These members also postponed multimorbidity since those who were already diagnosed with an age-related disease had a 54% lower risk of having a second age-related disease compared to their partners.

An increasing number of long-lived ancestors, as measured with the Longevity Relatives Count (LRC) score, not only associates with a lower mortality at any moment in life it also associates, in a similar way, with a lower disease incidence during mid and later life (60-75 years): With every 10% increase in LRC score the yearly risk to develop an age-related disease decreased with 5% in the LLS, and 6% in the SEDD, maximizing to 50% and 60% respectively when all ancestors were long-lived.