Biotech firm LyGenesis, Inc, which develops cell therapies that enable organ regeneration, announced today that the US Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application. Under the IND, LyGenesis will be conducting a Phase 2a study on the safety, tolerability, and efficacy of its first-in-class novel cell therapy for patients with end stage liver disease (ESLD). In addition, LyGenesis announced it has just completed over 11 million in private financing of convertible notes led by Juvenescence Ltd. and Longevity Vision Fund. Proceeds will be used to progress LyGenesis' Phase 2a clinical trial with a first patient in targeted for early 2021. The funds will also be used to develop LyGenesis' other cell therapies using lymph nodes as bioreactors to regrow functioning organs, including pancreas, kidney, and thymus regeneration.

"With cash on hand to run our Phase 2a trial, we can now focus on our next IND enabling preclinical programs, as our pancreas (for type I diabetes) and thymus (for aging as well as multiple orphan indications) cell therapy programs can now draft behind the regulatory precedent that we've set with our liver program. it's still a lot of work, but the resistance is just a little less and it enables you to go further, faster. The FDA clearance for our IND and the start of our Phase 2a study in patients with ESLD is a testimony to our robust preclinical research program, the unmet need in advanced liver disease, and our novel approach to organ regeneration. Moreover, the lack of genetic manipulation, ease of administration, and low cost of goods for our cell therapy forms the foundation for a promising and scalable first commercial product."

Senescent cells are the hallmark and therapeutic target of cellular senescence involved in a wide range of biological processes, including tumor suppression, embryonic development, wound healing and tissue repair, and aging. Although senescent cells are detrimental to the body during aging and can lead to chronic diseases, such as obesity, diabetes, and sarcopenia, they also suppress cancer and fibrosis.

Senolytics is a new class of medicines that target senescent cells, which has emerged rapidly in the past few years. Preclinical studies on rodents have been applied to explore the potential targets of senescent cells and the preliminary effects of senolytic medicine in vivo. In addition to transgenic mice, senolytic drugs, including dasatinib and quercetin, ABT263, and SSK1, showed the therapeutic effects on senescent cells and alleviated the radiation and age-related symptoms and pathology. Strikingly, two small clinical trials on senolytic treatments with dasatinib and quercetin were completed last year and reported therapeutic effects for patients with diabetic kidney disease (N = 9) and idiopathic pulmonary fibrosis (N = 14).

Physical exercise is widely recognized as a safe, effective, and cost-effective "medicine" for a broad range of age-related diseases. Moreover, a lack of exercise is a major contributing factor to accelerated aging and age-associated chronic conditions, including cancer, obesity, and cardiovascular diseases. A clearer delineation of anti-aging and anti-disease effects and underlying mechanisms of exercise is needed. While the accumulation of senescent cells has been identified as the mechanism of aging and multiple diseases for decades, senolytics targeting senescent cells has just been developed in recent years. In addition, exercise has shown its capacity to lower the marker of senescent cells over the past decade. In the current systematic review of all available literature, we explored the potential senolytic effects of exercise in both human and animal models under healthy or disease states. We aimed to improve the understanding of the cellular senescence-based mechanisms underlying exercise as anti-aging medicine.

The findings of this systematic review and meta-analysis provided some evidence that exercise may be a senolytic medicine for p16INK4a-positive senescent cells in humans and for p21Cip1-positive senescent cells in obese but not healthy animals. Future studies should examine the optimal form and dosage of exercise, targeted cells/tissues, different disease states, and the underlying cellular mechanisms in humans and animals. A greater understanding of the senolytic effects of exercise can lead to significant clinical and public health impact.

Today, there are over 130 longevity biotechnology companies and over 50 anti-aging drugs in clinical trials in humans. The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans. Whether we live to see anti-aging therapies to keep us alive indefinitely (i.e. whether we make it to longevity escape velocity) depends on how much traction and funding the field gets in coming decades.

Aging is essentially damage that accumulates over time, which exponentially increases the risk of the diseases that kill most people. This 'damage' associated with aging comes in essentially nine forms, known as the hallmarks of aging. These forms of cellular damage drive the increased risk of disease, frailty, cognitive decline as well as observable signs of aging such as grey hair and wrinkles. The 'damage' (hallmarks of aging) occurs as a by-product of normal metabolism - the biochemical reactions that keep us alive. More and more damage accumulates and eventually leads to pathology, i.e. disease. When we talk about anti-aging we are talking about fixing the damage using an engineering approach before it accumulates to a dangerous level at which diseases emerge.

Anti-aging is more feasible for extending healthy lifespan rather than solving the individual diseases of aging due to the Taueber paradox and the highly co-morbid nature of age-related diseases. Even if a person survives one age-related disease such as cancer, another (e.g. diabetes, cardiovascular disease) will kill them if aging is not solved. This accounts for the much smaller increase in healthy lifespan associated with curing the diseases of aging, such as cancer (2-3 years), versus slowing aging itself (30+ years). The difference between anti-aging and current medicine is the former prevents illness by targeting the hallmarks of aging, whereas the latter intervenes once a disease has emerged. If we compare current medical interventions associated with geriatrics with anti-aging - the former extends unhealthy lifespan, whereas only the latter extends healthy lifespan.

The past five years of research have demonstrated several anti-aging strategies as particularly promising. Heterochronic parabiosis is putting young blood into old mice, to make the old mice biologically younger. This is achieved in the lab by connecting the circulatory systems of young mice and old mice. Recently, a group of Russian biohackers recently performed the first plasma dilution experiments in humans. In a research context, the safety and effectiveness of apheresis is being tested in a clinical trial in humans by the company Alkahest.

Dietary restriction has been shown to extend healthy lifespan across several species. Drugs that mimic the metabolic effects of dietary restriction also have beneficial effects on lifespan. Nutrient-sensing biochemical pathways (such as IGF-1, mTOR, and AMPK) play a key role in these effects. Metformin is a drug that is FDA-approved for diabetes that extends healthy lifespan in mice by inhibiting mTOR and activating autophagy. Metformin is currently being tested in a large clinical trial in humans to test its anti-aging properties. Another promising drug that manipulates metabolism is rapamycin, an FDA-approved immunosuppressant that extends healthy lifespan in mice and similarly acts to inhibit mTOR. Rapamycin is currently in a clinical trial in humans to test its anti-aging properties.

Senescent cells are a kind of 'zombie'-like cell that accumulate with age. They are death-resistant cells that secrete proinflammatory factors associated with a range of age-related diseases. There are various strategies being explored to kill or reprogram senescent cells, including senolytics. Senolytics are drugs that kill senescent cells to improve physical function and healthy lifespan. When administered to older mice, senolytics have been shown to reverse many aspects of aging such as cataracts and arthritis. Killing senescent cells with senolytics extends the median healthy lifespan in mice. Several senolytics, such as the combination of dasatinib and quercetin, and fisetin are in clinical trials in humans today.

Cellular reprogramming is the conversion of terminally differentiated cells (old cells) into induced pluripotent stem cells (iPSCs) ('young' cells). Cells can be re-programmed to a youthful state using a cocktail of factors known as Yamanaka factors. iIPSCs have essentially unlimited regenerative capacity and carry the promise for tissue replacement to counter age-related decline. Partial reprogramming in mice has shown promising results in alleviating age-related symptoms without increasing the risk of cancer. An impressive example of cellular reprogramming was the restoration of vision in blind mice with a severed optic nerve using three of the four Yamanaka factors.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease, which is characterized by the aberrant accumulation of extracellular matrix (ECM) in the lung parenchyma and deterioration of lung function. Both clinical observations and epidemiological investigations indicate that IPF is an aging-associated disease, since IPF occurs primarily in middle-aged and elderly people (median age at diagnosis is around 65 years), and the incidence rises remarkably with advancing age.

Cellular senescence is pivotal for phenotype of aging. The characteristics of senescent cells include growth arrest, enlarged cell morphology, elevated activity of SA-β-Gal as well as increased expression of cell cycle inhibitors, such as p16 and p21. Dysfunctional re-epithelialisation, following repetitive micro-injury, initiates the process of pulmonary fibrosis (PF). Increasing evidences have implicated that accelerated senescence of alveolar epithelial cells, a main cause of epithelial dysfunction, plays an important role in IPF pathogenesis. Senescent alveolar epithelial cells not only lose the ability of regeneration and repair, but also exert deleterious effects on neighboring cells by secreting a variety of proinflammatory cytokines, pro-fibrosis factors, growth factors, matrix metalloproteinases, and chemokines, described as senescence-associated secretory phenotype (SASP).

Fisetin (FIS), a natural non-toxic flavonoid, is present in various plants, fruits, and vegetables. Previous research has demonstrated that FIS has anti-inflammatory, anti-fibrosis, anti-oxidant, and anti-aging properties. Senolytic drugs, dasatinib and quercetin (D + Q), can attenuate experimental PF via selective depletion of senescent alveolar epithelial cells. More encouragingly, a recent first-in-human open-label clinical trial has suggested that short-term administration of D + Q could improve the physical dysfunction in IPF patients. Both FIS and quercetin belong to the flavonoid class, and FIS exhibits stronger senotherapeutic activity in cultured cells than quercetin, and can extend lifespan in mice. These traits remind us that FIS may have protective effect in PF. However, the role of FIS in PF has not been elucidated.

Bleomycin (BLM)-induced PF is the most frequently used animal model. Treatment with BLM can also induce alveolar epithelial cell senescence in vitro and in vivo. In this study, BLM was used to reproduce PF in mice and induce alveolar epithelial cell senescence to investigate the effect and mechanism of FIS in experimental PF. We found that FIS treatment apparently alleviated BLM-induced weight loss, inflammatory cells infiltration, inflammatory factors expression, collagen deposition and alveolar epithelial cell senescence, along with AMPK activation and the down regulation of NF-κB and TGF-β/Smad3 in vivo. In vitro, FIS administration significantly inhibited the senescence of alveolar epithelial cells and senescence-associated secretory phenotype. FIS may be a promising candidate for patients with pulmonary fibrosis.

Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study.

In this study, we show that an increased rate of arterial stiffening is associated with lower white matter (WM) microstructural integrity and cerebral blood flow (CBF) in older age. Furthermore, these associations were present in diffuse brain areas, suggesting that exposure to excess pulsatility may result in a widespread damaging effect on the fragile cerebral microstructure. Cognitive function at follow-up related more closely with baseline arterial stiffness rather than rate of arterial stiffening. Taken together, these findings suggest that although faster rates of arterial stiffening in the transition to old age may negatively impact brain structure and function, long-term exposure to higher levels of arterial stiffness prior to this point may be the most important determinant for future cognitive ability.

While aortic stiffening has predominantly been studied in the context of CVD, recent evidence suggests that large artery dysfunction may also play a role in dementia. Indeed, patients with Alzheimer's disease and vascular dementia reportedly have higher levels of aortic stiffness relative to cognitively healthy adults. Aortic stiffening is a hallmark of vascular ageing and may lead to a heightened state of oxidative and inflammatory damage within the cerebral tissues due to an increased penetrance of excess pulsatility into the fragile microcirculation of the brain. These changes have been shown to disrupt endothelial cell function and the blood brain barrier in animal models and have also been hypothesised to compromise cerebral perfusion and ultimately lead to amyloid deposition, neurodegeneration, and cognitive impairment. While previous studies have related cross-sectional measures of arterial stiffness to cognition, this is the first study, to our knowledge, to publish associations between progressive increases in aortic stiffening over a 4-year period and cerebral and cognitive outcomes in later life.

Our findings suggest two things. First - and in agreement with previous studies linking modifiable risk factors to later adverse outcomes - early prevention strategies to reduce life-term exposure to risk factors may be required to in order to offer maximal benefits to later-life cognition, particularly in relation to domains such as semantic fluency and verbal learning. Second, novel to this study is our observation of additional relationships between faster rates of arterial stiffening during this period of life and the presence of pathological differences in WM structure and cerebral perfusion observed in the following years. We show for the first time that interventions to reduce or prevent the rapid increases in arterial pulsatility in mid-to-late life may reduce detrimental changes in WM integrity and blood flow, which have previously been linked to cognitive function, and may therefore also offer additional (albeit possibly more modest) benefits to cognitive ability in older age.

As the global population ages, there is increased interest in living longer and improving one's quality of life in later years. However, studying aging - the decline in body function - is expensive and time-consuming. And despite research success to make model organisms live longer, there still aren't really any feasible solutions for delaying aging in humans. With space travel, scientists and engineers couldn't know what it would take to get to the moon. They had to extrapolate from theory and shorter-range tests. Perhaps with aging, we need a similar moonshot philosophy. Like the moon once was, we seem a long way away from provable therapies to increase human healthspan or lifespan. This review therefore focuses on radical proposals. We hope it might stimulate discussion on what we might consider doing significantly differently than ongoing aging research.

A less than encouraging sign for many of the lifespan experiments done in preclinical models, namely in mammals such as mice, is that they have modest effect sizes, often only having statistically significant effects in one of the genders, and often only in specific dietary or housing conditions. Even inhibiting one of the most potent and well-validated aging pathways, the mechanistic target of rapamycin (mTOR) pathway has arguably modest effects on lifespan - a 12-24% increase in mice. This is all to ask, if the mTOR inhibitor rapamycin is one of the potential best-case scenarios and might be predicted to have a modest effect if any (and possibly a detrimental one) in people, should it continue to receive so much focus by the aging community? Note the problems in the aging field with small and inconsistent effects for the leading strategies aren't specific to rapamycin.

Treating individual aging-related diseases has encountered roadblocks that should also call into question whether we are on the optimal path for human aging. Alzheimer's is a particularly well-funded and well-researched aging-related topic where there are still huge gaps in our understanding and lack of good treatment options. There has been considerable focus on amyloid beta and tau, but targeting those molecules hasn't done much for Alzheimer's so far, leaving many searching for answers. The point is when we spend collectively a long time on something that isn't working well, such as manipulating a single gene or biological process, it should seem natural to consider conceptually different approaches.

The burden of influenza-related morbidity and mortality among older adults is substantial. Surveillance studies estimate that 71%-85% of influenza deaths occur in adults ≥65 years of age. Adults ≥65 years are 10 to 30 times more likely than younger adults to experience acute respiratory failure attributed to influenza disease. Low vaccine effectiveness among the elderly has been attributed to senescence of the immune system and a decreased immune response to vaccine antigens. Overlaid on age-related immunosenescence are the effects of frailty, a multi-dimensional syndrome marked by losses in function and physiological reserve. Physical frailty is characterized by diminished strength, endurance, and reduced physiologic function.

Physical frailty's impact on hemagglutination inhibition antibody titers (HAI) and peripheral blood mononuclear cell (PBMC) transcriptional responses after influenza vaccination is unclear. Physical frailty was assessed using the 5-item Fried frailty phenotype in 168 community- and assisted-living adults ≥55 years of age during an observational study. Blood was drawn before, 3, 7, and 28 days post-vaccination with the 2017-2018 inactivated influenza vaccine.

Frailty was not significantly associated with any HAI outcome in multivariable models. Compared with non-frail participants, frail participants expressed decreased cell proliferation, metabolism, antibody production, and interferon signaling genes. Conversely, frail participants showed elevated gene expression in IL-8 signaling, T-cell exhaustion, and oxidative stress pathways compared with non-frail participants. These results suggest that reduced effectiveness of influenza vaccine among older, frail individuals may be attributed to immunosenescence-related changes in PBMCs that are not reflected in antibody levels.

When a person consumes more calories than needed, the excess calories are stored in the form of triglycerides inside fat tissue, also known as white adipose tissue (WAT). Researchers know that in obese people, WAT becomes overworked, fat cells begin to die, and immune cells become activated. But the exact mechanism by which this inflammation occurs isn't fully understood. That chronic, low-level inflammation is one of the driving factors behind many of the diseases associated with obesity.

While many studies have focused on the signaling molecules produced by the fat cells or immune cells in WAT that might contribute to inflammation, this team of researchers took a different approach. They focused instead on the vessels that carry blood - as well as immune cells and inflammatory molecules - into WAT. In 2018, the team identified a new type of cell lining these blood vessels in mice - an adipose progenitor cell (APC), or precursor cell that goes on to generate mature fat cells. But unlike most APCs, the new cells, dubbed fibro-inflammatory progenitors, or FIPs, produced signals that encouraged inflammation. In the new work, the researchers looked more closely at the role of the FIPs in mediating inflammation.

Within just one day of switching young male mice to a high-fat diet, researchers discovered that the FIPs quickly increased the number of inflammatory molecules produced. After 28 days on a high-fat diet, they found a substantial increase in the proportion of FIPs compared with other APCs. To show that the increase in the number and activity of the FIPs was not just a side effect of already-inflamed fat cells, the team removed a key immune signaling gene, Tlr4, from the FIPs in some mice. After five months on a high-fat diet, the mice lacking Tlr4 had gained just as much weight, and just as much fat, as other mice on a high-fat diet. But the genetically engineered mice - with FIPs that could no longer generate the same signals - no longer had high levels of inflammation. Instead, the levels of inflammatory molecules in their WAT were closer to the levels seen in mice on low-fat diets.

Researchers went on to show that increasing levels of a related signaling molecule, ZFP423, in FIPs can also ameliorate the inflammation in mouse fat cells. The findings point toward possible avenues to pursue to lower the risk of disease in people with obesity.

Decline in biological resilience (ability to bounce back and recover) is a key manifestation of aging that contributes to increase in vulnerability to death with age, limiting longevity even in people without major diseases. Resilience is different from robustness which refers to the ability to avoid damage and its destructive consequences whatsoever. The robustness generally declines during aging; however, it may improve in some health domains, sometimes at the cost of resilience to future adverse events.

We propose that aging can be viewed as a combination of three universal components: (i) depletion of limited body reserves (e.g., of stem cells, immune cells, muscle cells, neural cells, etc.), which poses limits to recovery; (ii) slowdown of physiological processes and responses to stress/damage, which delays the recovery with age; and (iii) inherently imperfect mechanisms of cell/tissue repair and cleaning, which result in incomplete recovery and damage accumulation over time. These aging components together create the age-decline in resilience, which in turn contributes to increase in mortality risk with age eventually limiting longevity even in people without major diseases.

These aging components can be seen in all aging animals, albeit their relative contributions to the decline in resilience, as well as to longevity limits, may differ across species, which could contribute to the variability of longevity and pace of aging among the species and strains. This may also be a reason why the effects of anti-aging interventions observed in lab animals are not always replicated in humans. There are open questions about relative impacts of the different aging components on the decline in resilience and the increase in mortality risk with age. However, the area develops quickly, and prospects are encouraging.

Finding the 'optimal' anti-aging intervention that could oppose the decline in resilience and also extend the species longevity limits remains a challenging problem. To be more efficient, the anti-aging interventions may need to target several aging components at once, e.g., help replenish body reserves, enhance cell repair and tissue cleaning, and attenuate the slowdown of metabolism, proliferation, and information processing, simultaneously.

It's often argued that life expectancy across the world has only increased because child mortality has fallen. If this were true, this would mean that we've become much better at preventing young children from dying, but have achieved nothing to improve the survival of older children, adolescents and adults. Once past childhood, people would be expected to enjoy the same length of life as they did centuries ago. This is untrue. Life expectancy has increased at all ages. The average person can expect to live a longer life than in the past, irrespective of what age they are.

The most striking development is the dramatic increase in life expectancy since the mid-19th century. Life expectancy at birth doubled from around 40 years to more than 81 years. This achievement was not limited to England and Wales; since the lattter part of the 19th century life expectancy doubled across all regions of the world. The evidence that we have for population health before modern times suggest that around a quarter of all infants died in the first year of life and almost half died before they reached the end of puberty and there was no trend for life expectancy before the modern improvement in health: life expectancy at birth fluctuated between 30 and 40 years with no marked increase ever.

A common criticism of the statement that life expectancy doubled is that this "only happened because child mortality declined". I think that, even if this were true, it would be one of humanity's greatest achievements, but in fact, this assertion is also just plain wrong. Mortality rates declined, and consequently life expectancy increased, for all age groups. In 1841 a five-year-old could expect to live 55 years. Today a five-year-old can expect to live 82 years. An increase of 27 years. The same is true for any higher age cut-off. A 50-year-old, for example, could once expect to live up to the age of 71. Today, a 50-year-old can expect to live to the age of 83. A gain of 13 years.

A tremendous growth in the proportion of elderly people raises a range of challenges to societies worldwide. Healthy aging should therefore be a main priority for all countries across the globe. However, science behind the study of age-associated diseases is increasing and common molecular mechanisms that could be used to dissect longevity pathways and develop safe and effective interventions for aging are being explored. The 7th Annual Aging Research and Drug Discovery (ARDD) meeting was held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy.

Molecular and therapeutic importance of NAD+ metabolism for aging was underlined in multiple talks at the ARDD meeting. Eric Verdin, Buck Institute, USA introduced the concept of competition among major NAD+-utilizing enzymes for NAD+ that may explain its age-dependent decline across multiple tissues. Evandro Fei Fang, University of Oslo, Norway underlined the importance of the NAD+-mitophagy / autophagy axis in aging and neurodegeneration and presented data on how impairment of this axis contributes to the progression in accelerated aging diseases as well as in the most common dementia, the age-predisposed Alzheimer's disease.

Another recently uncovered molecule that is able to improve mitochondrial function via mitophagy is Urolithin A, a gut microbiome metabolite known to improve mitochondrial function via mitophagy, increases muscle function, and possesses geroprotective features across multiple species. Pénélope Andreux, Amazentis, Switzerland presented results from a double blinded placebo controlled study showing that urolithin A administration in healthy elderly people is safe and was bioavailable after single or multiple doses over a 4-week period. Oral consumption of urolithin A decreased plasma acylcarnitines, a sign of improved systemic mitochondrial function, and displayed transcriptomic signatures of improved mitochondrial and cellular health in muscle.

Notably, studies of multiple interventions in different aging models include examinations of various markers of cellular senescence. Its significance for the aging process has been shown multiple times across model systems. Senescent cells occur in all organs, including post-mitotic brain tissues, during aging and at sites of age-related pathologies. The SASPs of senescent cells lead to chronic inflammation and may contribute to the development of various cellular phenotypes associated with aging and diseases. Hence, a novel class of drugs targeting senescent cells are emerging, including senolytics (selective elimination of senescent cells) and senomorphics (selective modification of senescent cells).

Several strategies were proposed to target senescent cells. Marco Demaria, ERIBA, Netherlands, demonstrated the important role of oxygen in the development of the senescence phenotype. Data illustrated that growth arrest, lysosomal activity and DNA damage signalling were similarly activated in senescent cells cultured at 1% or 5% oxygen, but induction of the SASP was suppressed by low oxygen. Tissues exposed to low oxygen also expressed a lower SASP than more oxygenated ones. It was demonstrated that hypoxia restrains SASP via AMPK activation and mTOR inhibition, and that intermittent treatment with hypoxia mimetic compounds can serve as a potential strategy for the reduction of SASP in vivo.

Current knowledge shows that aging is a very complex but plastic process. Conserved molecular pathways underlining aging can be manipulated using genetic, pharmacological, and non-pharmacological approaches to significantly improve the healthspan and lifespan in model organisms, and perhaps humans. A collaborative effort between academic research with a growing number of emerging biotech companies, as well as increased investment funds to accelerate discoveries, will most likely bring effective aging pharmaceuticals in the near future.

The author began professional life as a physicist. As a child, he was fascinated by space, the way many scientists are. But he has spent the past three years researching a book about biogerontology, the scientific study of ageing, in which he argues the case for a future in which our lives go on and on. He considers ageing "the greatest humanitarian issue of our time". When he describes growing old as "the biggest cause of suffering in the world," he is being earnest.

In the past three decades biogerontological research has accelerated, and recent successes have sparked excitement. A 2015 study, published by the Mayo Clinic, in the US, found that using a combination of existing drugs - dasatinib, a cancer medicine, and quercetin, which is sometimes used as a dietary suppressant - to remove senescent cells in mice "reversed a number of signs of ageing, including improving heart function". A 2018 study that used the same drugs found that the combination "slowed or partially reversed the ageing process" in older mice. After the success in mice, the first trial aimed at removing senescent cells in humans began in 2018, and others are ongoing. "This collection of evidence is tantalising, and foreshadows a future where ageing will be treated. Scientists are rightly sceptical, but it's important to say that a lot of significant breakthroughs could happen in the lifespan of people alive today."

When the author brings up his work with people, the question he gets asked most often is: "What about overpopulation?" He has a go-to answer he thinks highlights the ridiculousness of the question. "Imagine we're staring down the barrel of 15 billion people on Earth. There are lots of ways to try and tackle that problem. Would one of them be: invent ageing?" That he is asked this question so frequently frustrates him. More so, he is bothered by the implication that what he is suggesting is somehow weird or inhuman or unholy, rather than ultimately helpful for society. "If I'd just written a book about how we're going to cure childhood leukaemia using some amazing new medicine, literally nobody would be like, 'But isn't that going to increase the global population?'"

He shakes his head. "What I'm saying is, 'Here is an idea that could cure cancer, heart disease, stroke...' Curing any one of those things would get you plaudits. But as soon as you suggest a potentially effective way of dealing with them altogether, suddenly you're some mad scientist who wants to overpopulate us into some terrible environmental apocalypse?" The author considers this a major hurdle in biogerontology's potential success - our "incredible bias toward the status quo" of ageing as an inevitable process, and our inability to accept it as preventable. "If we lived in a society where there was no ageing, and suddenly two-thirds of people started degenerating over decades, started losing their strength, started losing their mental faculties, and then succumbing to these awful diseases, it would be unthinkable. And of course, we'd set to work trying to cure it."

As the main purpose of senotherapy is to kill scenescent cells (SCs), safe and effective detection and targeting of these cells is crucial to improving human health and prolonging lifespan. Nano-based systems developed to identify and kill senescent cells can be considered as second-generation targeted and selective senolytics that are able to efficiently eliminate senescent cells upon systemic administration without causing adverse side effects. One of the best-explored groups of nano-senolytics is smart nanodevices that are based on porous calcium carbonate nanoparticles, mesoporous silica nanoparticles, carbon quantum dots, and molecularly-imprinted polymer nanoparticles (nanoMIPs).

Targeted delivery and detection / elimination of SCs can be achieved by encapsulation of senolytics / senomorphics / fluorophores using a number of nanomaterials. For example, cargo release in the presence of β-galactosidase (β-gal) was due to the hydrolysis of the capping galacto-oligosaccharide (Gal) polymer. In vitro studies demonstrated that nanomaterials covered with Gal and loaded with fluorophores (e.g., rhodamine B, indocyanine green, coumarin-6, or Nile blue) were preferentially activated in β-galactosidase-overexpressing SCs, which were able to lyse the galacto-oligosaccharide coat. Moreover, β-galactosidase-instructed supramolecular assemblies can also lead to the formulation of hydrogels and nanofibers in SCs, which decreases the expression of senescence-driving proteins.

Apart from β-gal, increased expression of other lysosomal hydrolases (e.g., α-L-fucosidase) has been used for detection of senescent cells. To date, a collection of senoprobes has been described. Nano-based senoprobes could be utilized to monitor the response of tumors to the administration of senescence-inducing chemotherapeutic drugs. More recently, another method for the real-time in vivo detection of senescent cells based on mesoporous silica nanoparticles loaded with Nile blue and coated with a galacto-hexasaccharide was proposed. Functionalized nanomaterials appear to have a promising potential as nanocarriers and can be used for improving SC clearance.

A cancer-specific L-type amino acid transporter 1 (LAT1) is highly expressed in cancer tissues. Inhibiting the function of LAT1 has been known to have anti-tumor effects, but there has been limited progress in the development of radionuclide therapy agents targeting LAT1. Now, a research team has established a targeted alpha-therapy with a novel drug targeting LAT1.

The researchers first produced the alpha-ray emitter 211-Astatine, no easy task given that Astatine (At) is the rarest naturally occurring element on Earth. Targeted alpha-therapy selectively delivers α-emitters to tumors; the advantage over conventional β-therapy is that alpha decay is highly targeted and the high linear energy transfer causes double-strand breaks to DNA, effectively causing cell death. The short half-life and limited tissue penetration of alpha radiation ensures high therapeutic effects with few side-effects to surrounding normal cells.

Next, to carry the radioisotope into cancer cells, the researchers attached it to α-Methyl-L-tyrosine, which has high affinity for LAT1. This subterfuge exploits the elevated nutrient requirements of rapidly multiplying cancer cells. "We found that 211At-labeled α-methyl-L-tyrosine (211At-AAMT) had high affinity for LAT1, inhibited tumor cells, and caused DNA double-strand breaks in vitro. Extending our research, we assessed the accumulation of 211At-AAMT and the role of LAT1 in an experimental mouse model. Further investigations on a human pancreatic cancer cell line showed that 211At-AAMT selectively accumulated in tumors and suppressed growth. At a higher dose, it even inhibited metastasis in the lung of a metastatic melanoma mouse model."

Biological aging is the greatest risk factor for nearly every major cause of death and disability in developed countries, and new insights into the aging process may fundamentally change the way we approach human health. From basic research on the cellular and molecular hallmarks of aging to the next generation of "aging clocks" to potential clinical interventions, watching back the symposium recording presents an opportunity to hear the very latest from scientists in this field.

From Peter Fedichev of GERO: Heritability of human lifespan is 23-33% as evident from twin studies. Genome-wide association studies explored this question by linking particular alleles to lifespan traits. However, genetic variants identified so far can explain only a small fraction of lifespan heritability in humans. Here, we report that the burden of rarest protein-truncating variants (PTVs) in two large cohorts is negatively associated with human healthspan and lifespan, accounting for 0.4 and 1.3 years of their variability, respectively. In addition, longer-living individuals possess both fewer rarest PTVs and less damaging PTVs. We further estimated that somatic accumulation of PTVs accounts for only a small fraction of mortality and morbidity acceleration and hence is unlikely to be causal in aging. We conclude that rare damaging mutations, both inherited and accumulated throughout life, contribute to the aging process, and that burden of ultra-rare variants in combination with common alleles better explain apparent heritability of human lifespan.

From Hosni Cherif of McGill University: Intervertebral disc (IVDs) degeneration is one of the major causes of back pain. Cellular senescence is a state of stable cell cycle arrest in response to a variety of cellular stresses including oxidative stress and DNA damage. The accumulation of senescent IVD cells in the tissue suggest a crucial role in the initiation and development of painful IVD degeneration. Senescent cells secrete an array of cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP). The SASP promote matrix catabolism and inflammation in IVDs thereby accelerating the process of degeneration. This study demonstrates the potential of a natural (o-Vanillin) and a synthetic (RG-7112) senolytic compounds to remove senescent IVD cells, decrease SASP factors release, reduce the inflammatory environment and enhance the IVD matrix production. Removal of senescent cells, using senolytics drugs, could lead to improved therapeutic interventions and ultimately decrease pain and a provide a better quality of life of patients living with intervertebral disc degeneration and low back pain.

From Ying Ann Chiao of Oklahoma Medical Research Foundation: Mitochondrial dysfunction plays a central role in aging and cardiovascular disease. However, it was unclear whether improving mitochondrial function at late-life can rescue pre-existing age-related cardiac dysfunction, especially diastolic dysfunction. Here, we show that 8-week treatment with a mitochondrial-targeted peptide SS-31 (elamipretide) can substantially reverse pre-existing cardiac dysfunction in old mice. At molecular levels, late-life SS-31 treatment reduces mitochondrial ROS levels and normalizes age-related increases in mitochondrial proton leak and protein oxidative modifications. Late-life viral expression of mitochondrial-targeted catalase (mCAT) similarly improves diastolic function in old mice. SS-31 treatment cannot further improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. Our results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and support the therapeutic potentials of mitochondrial-targeted interventions in cardiac aging.