On the subject of Juvenescence, I am off to San Francisco with my old best friend Anthony Baillieu to meet my new best friend Aubrey de Grey (Google him!) and my dear colleague Greg Bailey. We are all spending the day at the Buck Institute of Aging - not to be rejuvenated ourselves, but to understand more of the amazing science that is coming out of this institution.

One of the key senolytic drugs in development, being trialled by Unity Biotechnology, first emerged at the Buck. In a nutshell, senolytics are among the first of several compounds that will add significantly to human lifespan in the next ten or twenty years. While more fully described in the new book, these are drugs that clear so-called senescent cells from tissues. Senescent cells become more prevalent as we age, and are cells that are neither dead nor healthy, but which exist in a limbo like state. They contribute significantly to inflammatory disease and their removal, at least in part, is demonstrably life extending in animal models.

We are also visiting another company involved in senolytics, and will be looking to make an investment in it for our venture, Juvenescence Limited, which is jointly owned by Greg, Dec Doogan (formerly head of drug development at Pfizer, the world's biggest drug company) and myself. We have collectively recently invested a largish sum in a venture called Insilico Medicine, which uses deep neuronal networks (aka AI) to enhance medical discoveries, and we have capitalised a joint venture with Insilico called Juvenescence AI which will look to discover five new chemical entities a year for several years, using AI. These are exciting times in the field of longevity, and believe me, staying healthy today will allow you to cross a bridge to ultra-long life in the not too distant future.

You recently said that you "predict we are about to end the aging process. In the next five years no less!" Whilst progress has indeed been rapid in the field of rejuvenation biotechnology, could you clarify, is this five years to achieving this in human cells, to clinical trials or what exactly?

Within five years it seems plausible to have some gene therapies in FDA approved clinical trials in dogs - aimed at general aging reversal, but quite likely, labeled for specific diseases (and in humans soon thereafter). This means combinations of gene therapies aimed at most of the known major aging pathways, though there are major challenges in efficient delivery.

Do you agree that epigenetic alterations as described in the Hallmarks of Aging are a primary driver of the aging process, and if so do you think we can safely use cell reprogramming factors OSKM (OCT4, SOX2, KLF4 and MYC) to turn back cellular aging?

Yes. Epigenetics are important drivers, but it are only part of the Hallmarks of Aging - and OSKM would, in turn, be only part of that. Other examples are factors behind heterochronic parabiosis. Efficacy may depend on the various tissue types.

DNA damage is proposed to be a primary reason we age. Can it be repaired by targeting TFAM (Transcription factor A, mitochondrial precursor) to increase NAD (a coenzyme in all living cells that facilitates the production of energy) levels that are known to facilitate DNA repair?

We have targeted TFAM and consequently raised NAD successfully. The NAD-facilitated repair is not the only route - we can prevent DNA damage (via the management of radical oxygen species), prevent the impact of such damage (e.g. duplicating tumor suppressor genes), favor specific types of DNA repair, or induce apoptosis in cells which appear to acquire potentially oncogenic mutations.

Cancer is caused by an unstable genome resulting from DNA damage and could be considered the poster child of aging diseases, can we use CRISPR to defeat cancer?

Genome editing (TALENs, CRISPR, etc.) and transgenic methods (CART) are being 'successfully' applied, but proof of generality and long remission is not here yet. Effective alternatives are preventative - vaccines against some of the 11 infectious, cancer-causing agents (e.g. HPV), inherited genome sequencing, genetic counseling, prophylactic surgery and avoiding environmental risk factors. Some strategies which work to preventatively reduce cancer in mice might benefit from engineering germline or more efficient delivery of gene therapies (since single untreated cells matter more for cancer than other diseases).

Do you think we can learn useful knowledge that can be applied to humans from the whole-genome sequencing of long lived species such as the 400-year-old greenland shark?

The most promising sequencing insights will probably come from genomes closest to average humans, such as naked mole rat, bowhead whales and human supercentenarians. Even more crucial is low-cost, high-accuracy testing of hypotheses flowing from those sequences, plus already hundreds of hypotheses from model organisms and cell biology (see the GenAge database).

The dream of fending off old age is as old as human civilization. Given the global aging of the population, developing interventions that preserve health in old age and postpone the onset of age-related diseases is more important than ever. In addition, we now know that it is possible to retard aging in animal models. Various genetic, dietary, and pharmacological interventions have been shown to increase lifespan, in some cases dramatically (tenfold is the current record), in short-lived model organisms like yeast, worms, flies, killifish, mice, and rats. Importantly, life-extending interventions not only increase longevity but can retard the onset of age-related diseases, resulting in the extension of healthspan (i.e., the length of time one lives in good health). These breakthroughs in the biology of aging and its impact on health and disease, referred to by some as 'geroscience', have led to the promise that we will be able to delay or slow human aging, resulting in unprecedented health benefits.

Leading causes of death worldwide, and notably in industrialized countries, are age-related diseases like cardiovascular diseases, cancer, and neurodegenerative diseases. Because of the strong relationship between the aging process and age-related diseases, the benefits emerging from anti-aging science have enormous potential. Using a model of future health and spending in the USA, the effect of delayed aging resulting in 2.2 years additional life expectancy would yield 7 trillion in savings over 50 years; whereas addressing single pathologies such as cancer and heart disease would yield less, mostly due to competing risks. Given its huge potential financial benefits, anti-aging science has tremendous commercial opportunities. The anti-aging industry has struggled in the past in terms of reputation, but driven by more recent scientific breakthroughs it has been growing substantially with several young companies supported by world-leading brands.

As with most diseases, traditional pharmacological approaches are the most straightforward and widely explored way to target aging. Notable examples of anti-aging drug discovery efforts include pharmacological manipulations of sirtuins, sirtuin 1 (SIRT1) in particular (targeted by resveratrol), and TOR (targeted by rapamycin), which are currently being explored. TOR inhibition by rapamycin results in increased lifespan from yeast to mammals. In a small but groundbreaking clinical trial by Novartis, rapamycin improved immune function in elderly volunteers. Because rapamycin has various side effects, companies and laboratories are trying to develop safer analogs, known as 'rapalogs'. Research on resveratrol and sirtuins was high profile in 2008 when GlaxoSmithKline (GSK) purchased the sirtuin-focused biotech company Sirtris (based on work at Harvard Medical School) for 720 million. Enthusiasm for resveratrol and sirtuins as anti-aging compounds has arguably declined in more recent years. Briefly, results have been largely disappointing since then. While Sirtris demonstrated that anti-aging biotech companies could rapidly grow in value and become a financial success for founders and early investors, its more recent problems might have hurt subsequent anti-aging science-based enterprises by discouraging investors and entrepreneurs.

Antioxidants have been historically a major focus of the field. However, currently the idea that antioxidant pathways play a major role in aging is being challenged, and epidemiological studies have largely failed to support the supposed benefits of antioxidants. While many dietary supplements still focus on antioxidants, few companies in the field maintain such a focus.

Telomeres, the protein-bound structures at the ends of chromosomes, shorten with cell division and, at least in some tissues, with age. Although genetic manipulations of telomerase in mice have yielded conflicting results, one study found that overexpression of telomerase in adult mice led to a 24% increase in median lifespan while not increasing the incidence of cancer. Therefore, the idea of activating telomerase as anti-aging remains a powerful one, even resulting in one self-experiment using gene therapy by BioViva.

Telomere shortening, as well as various stressors, can cause proliferating cells to stop dividing and enter a proinflammatory senescent state. There is evidence that senescent cells accumulate with age, at least in some tissues. In a landmark study, drug-induced clearance of p16Ink4a-positive cells (a marker of senescence) once per week from age 1 year extended the median lifespan in two normal strains of mice by 24-27%. Tumorigenesis and age-related deterioration of heart and kidney were delayed or slowed. As a consequence, Unity Biotechnology, a company founded by researchers at the Mayo Clinic involved in the above-mentioned work as well as the Buck Institute, has raised 116 million from investors to develop senolytic (i.e., an agent that destroys senescent cells) treatments. Continuing research by the cofounders has focused on senolytic agents, including the killing of senescent fibroblasts with piperlongumine and ABT-263. Interestingly, they have also acquired a patent related to a senescent cell antibody for imaging and delivery of therapeutic agents.

Other companies focusing on senolytics include Oisin Biotechnologies, although, according to their website, they seem to be developing a genetically targeted intervention to clear senescent cells, suggesting a different approach than Unity. Moreover, Everon Biosciences has shown that a significant portion of cells with p16Ink4a expression may be a subclass of macrophage termed senescent associated macrophages (SAMs). Following this discovery Everon has announced that they will focus on these SAMolytic agents. Last, Siwa Therapeutics' focuses on developing antibodies against senescent cell markers capable of identifying and removing senescent cells.

With a decidedly Silicon Valley-based confidence, venture-capital funded big-data approaches are being pursued in aging and longevity science. High-profile players include Calico and Human Longevity Incorporated (HLI). Started as one of Google's moonshot projects in 2013, Calico is attempting to harness big data to improve understanding of the basic biology that controls lifespan. Not much is known about how this will look in practice. HLI is focused more directly on data than Calico and aims to create the largest database of integrated high-throughput assays - genotype, transcript, and microbiome data - along with deep phenotypic data on patients to fully map genotype to phenotype to inform health care in general. Published efforts have focused on deep sequencing of human genomes. Other companies are using big-data techniques to find new uses for already approved drugs. For one project Insilico Medicine uses deep learning on multiple 'omics' data types to find new relationships between existing drugs and gene regulatory pathways effected in, or otherwise related to, aging-related diseases.

In addition to reasons for spending on basic research in general, anti-aging science has unusual potential to benefit from market forces due to particularly favorable demographics. The median wealth of US families aged 62 years or older is over 200,000, compared with 100,000 and 14,000 for middle-aged and young families, respectively. This may in part be responsible for the increase in investment in even non-traditional therapies and direct to consumer (DTC) products and services aimed at extending healthy lifespan. One high-profile DTC company is Elysium Health, which sells its Basis pill directly to consumers. Basis contains an NAD+ precursor, nicotinamide riboside, that declines with age and is required for sirtuin activity. Elysium has already concluded a preregistered, 2-month randomized, double-blind Phase I trial for Basis using 120 healthy 60-80-year-olds. While results have yet to be published, a company press release claims that participant's blood NAD+ levels were increased by 40% for the duration of the second month. However, the release did not mention the results for health measures.

Caloric restriction (CR) is the most studied and most consistent intervention that increases both health- and lifespan. While a CR diet is too harsh for most people, intermittent fasting (IF) has been proposed as a less-restrictive alternative. Based on this premise, L-Nutra was created to develop and market proprietary fasting-mimetic meals designed to provide the beneficial effects of IF.

A growing number of companies are now focusing on anti-aging science. In a way this is surprising, given that the first high-profile anti-aging company, Sirtris, while a success as an early investment has thus far failed to live up to its anti-aging expectations. Modern advances, abundant aging-related targets and an aging population can arguably be driving the current crop of anti-aging biotechs, but how realistic is it that these will succeed? In a sense there are few assumptions of which we can be confident. At present we can state that: (i) aging is a complex process; (ii) although there are numerous theories of aging with vocal advocates, there is no consensus among scientists regarding the underlying causes of aging; and (iii) aging can be manipulated in short-lived model systems by genetic, dietary, and pharmacological intervention. However, that leaves many open questions, so the uncertainty concerning human anti-aging approaches remains very high.

Although findings from short-lived model organisms, particularly in terms of the plasticity of aging, have been a major breakthrough in the field, the degree to which they are relevant to humans is unknown. Human homologs of genes associated with aging in model organisms have been associated with human longevity in some cases, but these are rare and thus our understanding of the genetic basis of human longevity remains largely unknown. Therefore, it is plausible that most findings from short-lived model organisms will not be relevant to human beings. Briefly, not only may the pathways necessary to extend lifespan in model systems be often irrelevant to the comparatively long-lived human species. Given the above concerns, a major open question is how effective anti-aging interventions can be in humans. Even if they have benefits, how do these compare with mundane lifestyle choices like going to the gym?

Of the 4000 private and 600 public biotech companies worldwide, only a few percent have shown increasing profitability. Historically, only one in 5000 discovery-stage drug candidates obtain approval and only a third of those recoup their R&D costs. Besides, the success rate of clinical trials is not improving, although we have more information, data, and potential targets than ever before. Given the various constraints on the study of aging, including the reliance on short-lived model organisms, long validation times, and poor biological understanding, it would be surprising if most of the companies described here are active a mere 5-10 years from now. Likewise, most companies in the anti-aging biotech sector are startups, and thus riskier. From an investor's perspective this means that investors in anti-aging biotech are expecting to lose money but hoping to win big.

Omics approaches are imperative, as is a multidisciplinary outlook, but while these have augmented the search space, attrition rates remain very high. Perhaps surprisingly, despite the so-far failure of Sirtris, which would be expected to hurt the industry, anti-aging biotech is more vibrant than ever. Clearly even such high-profile failure has not dissuaded investors, including many tech billionaires. No doubt new technologies will be developed and new targets discovered in the coming years and decades, possibly opening new avenues for the commercialization of aging in other directions. The promise of fending off old age remains more powerful than ever and the financial gains for any company delivering on that promise will continue to be extremely attractive. Anti-aging biotech can then be seen as an extreme reflection of the biotech sector: risky and most likely to fail, but if one company is successful the outcomes are monumental.

Researchers have found cell receptors abnormally overexpressed in post-mortem brains of those with Parkinson's and Alzheimer's diseases, and that they can be inhibited in animal models to clear toxic protein buildup, reduce brain inflammation, and improve cognitive performance. These dual findings mark the first time that the receptors, discoindin domain receptors (DDRs), have been understood to play a role in Parkinson's and Alzheimer's diseases. They are primarily known as potential targets against cancer. "Activation of these cell receptors appear to prevent brain cells from cleaning out the trash - the toxic buildup of proteins, such as alpha-synuclein, tau and amyloid, common in neurodegenerative diseases."

When DDRs are over-expressed, their actions become destructive. One reason may be that DDRs are protein enzymes known as tyrosine kinases that act as on and off switches of the cell self-cleaning process known as autophagy. Excess DDRs activation may switch off autophagy, resulting in build-up of toxic proteins inside brain cells and possibly breakdown of the blood-brain barrier, common in neurodegenerative diseases. DDRs inhibition with a tyrosine kinase inhibitor appears to insulate the brain via blood-brain barrier repair, which prevents harmful immune cells that circulate in the body from getting into the brain where they can indiscriminately attack and kill healthy and sick neurons, like those that have been unable to perform autophagy. "We studied an experimental tyrosine kinase inhibitor that enters the brain and inhibits DDRs. Inhibition of these receptors with a low dose of the agent, LCB-03-110, or reduction of DDRs expression in several models of Parkinson's and Alzheimer's disease, allows nerve cells to switch on autophagy to clear toxic proteins and help the brain insulate itself from circulating inflammatory cells. This led to cognitive improvement in our animal models."

New research shows that the APP gene variant protecting against Alzheimer's disease significantly decreases plasma beta-amyloid levels in a population cohort. This is a significant discovery, as many on-going drug trials in the field of Alzheimer's disease focus on decreasing beta-amyloid levels in the brain tissue. According to the study, the APP A673T gene variant, which is a variant in the amyloid precursor protein gene protecting against Alzheimer's disease, leads to an average of 30 per cent decreased levels of the beta-amyloid subtypes 40 and 42. The effects of this previously discovered gene variant were analysed by utilising data from the METSIM (METabolic Syndrome In Men) study.

Approximately 0.3% of the population are carriers of the APP A673T gene variant. Although the variant itself is rare, the observed association with decreased plasma beta-amyloid levels is important from the viewpoint of Alzheimer's drug trials. Several on-going drug trials for Alzheimer's disease focus on decreasing beta-amyloid levels in the brain tissue. The findings from the population cohort in eastern Finland show that a life-long decrease in beta-amyloid levels is not associated with detrimental effects on lipid or glucose metabolism, or on any other metabolically relevant events.

Scientists have identified a couple of crucial steps in the formation of a protein called amyloid beta, which accumulates in clumps, or "plaques," in the brains of people with Alzheimer's disease. Those discoveries inspired efforts at disrupting the biochemical carving of amyloid beta's precursor protein into its final, toxic shape. The latest drugs being tested try to silence an enzyme, called BACE1, that cuts the precursor protein. But BACE1 has other functions that are beneficial, so stopping it altogether could bring unwanted side effects - including disrupting the production of myelin, the protective insulation of brain cells. Researchers have found that changing where the cut is made - in effect, guiding the enzyme's scissors to a different point - could achieve the same goal, with less collateral damage.

Researchers built upon two discoveries in the past decade of two rare mutations: one, found in Italian people, that leads to early onset Alzheimer's disease, and another, found in Icelandic people, that staves off Alzheimer's disease. The team was particularly intrigued by the diametrically opposite effects of both mutations because they affected the same point on the precursor protein's chain of 770 amino acids, swapping one acid for another. The researchers injected one set of mice with a virus carrying the Italian gene mutation, and another set with the Icelandic mutation. They found that the amino acid substitution affected where the precursor protein was cleaved. The Icelandic mutation resulted in a shortened form of amyloid beta, which does not become "sticky" and turn into plaque. The Italian mutation produced a longer, "stickier" version of amyloid beta, which ultimately becomes neuron-smothering plaque. Actually, the effects were a matter of degree: Each mutation led to more cuts in one location or more cuts in the other location. But in the gradual degradation of Alzheimer's disease, that could be enough - reducing the levels of the offending toxin could translate into many more years of life before cognitive decline sets in.

Pulmonary fibrosis causes the patient's lung tissue to scar, resulting in progressive pulmonary function deterioration. In particular, the surface of the alveoli (called the alveolar epithelium) is often affected. If the disease's origin is unknown, the condition is called idiopathic pulmonary fibrosis, or IPF for short. "The treatment options for IPF have been few and far between. We are therefore attempting to understand how the disease comes about so that we can facilitate targeted treatment." In the current work, researchers have now succeeded in solving another piece of the puzzle. "In both the experimental model and in the lungs of IPF patients, we were able to show that some cells in the alveolar epithelium have markers for senescence. Because the occurrence of IPF increases with age, this was already suspected. We have now succeeded in proving this hypothesis."

Senescence impairs lung function in two ways: It prevents lung cells from dividing when they need to be replaced. And senescent cells secrete mediators that further promote fibrosis. Since this effect also plays a role in cancer, the scientists were able to access an already existing group of medicines, the so-called senolytic drugs that selectively kill off senescent cells. In order to test possible treatment strategies, the scientists placed the affected cells into a three-dimensional cell culture and examined the drugs's effect ex vivo. "We observed that this caused a decline in the quantity of secreted mediators and additionally a reduction in the mass of connective tissue proteins, which are greatly increased in the disease." Altogether, the study shows that senescence in the cells of the alveolar epithelium can contribute to the development and worsening of IPF.

The incidence of idiopathic pulmonary fibrosis (IPF) increases with age and accumulating evidence strongly suggests ageing as a crucial contributor to IPF initiation and progression. In support of ageing as one proposed driver of disease pathogenesis, normal and accelerated-aged mice are more susceptible to experimentally induced fibrosis. A landmark paper in 2013 described nine hallmarks of ageing, and importantly, all nine hallmarks have been found to contribute to IPF pathogenesis, albeit to a variable degree. Cellular senescence, representing one of these hallmarks, is characterised by stable cell cycle arrest accompanied by secretion of mediators, including pro-inflammatory cytokines and metalloproteinases, collectively termed the "senescence-associated secretory phenotype" (SASP). While the detrimental effects of senescence are thought to be a result of stem or progenitor cell depletion or of the SASP components, senescence has also been described to be beneficial in tumour suppression and wound healing.

In the lung, as in other organs, the number of senescent cells increases with age and cellular senescence has been linked to the pathogenesis of chronic lung diseases such as chronic obstructive pulmonary disease or IPF. The contribution of senescent cells to disease onset and progression remain unclear. Some studies have suggested a link between increased senescence and fibrotic burden, while others report that attenuation of lung fibrosis correlates with lung fibroblast senescence. In addition to lung fibroblasts, evidence has emerged that alveolar epithelial cells can become senescent in IPF. However, lung epithelial cell senescence and its potential pathogenic role in IPF remains largely unexplored. Here, we aimed to investigate whether senescence of this cell population is detrimental or beneficial to lung repair. We utilised senolytic drugs on fibrotic lung epithelial cells in vitro and ex vivo in three-dimensional lung tissue cultures and demonstrated that senolytic treatment attenuates fibrotic mediator expression, while stabilising epithelial cell marker expression and function. These findings suggest that senescence contributes to development of lung fibrosis and that treatment of pulmonary fibrosis with senolytic drugs might be beneficial.

When British billionaire Jim Mellon wants to map out an investment strategy, he likes to write a book first. Out of that process came his most recent work - Juvenescence: Investing in the Age of Longevity. Now he and some close associates with some of the best connections in biotech are using the book as inspiration to launch a new company - also named Juvenescence - with plans to make a big splash in anti-aging research. "We are at an inflection point for the treatment of aging," says Greg Bailey, who likes to highlight some of the new cellular pathways that are pointing to new therapies that can counter the effects of aging. "I think this is going to be the biggest deal I've ever done. It will need repetitive financing. Five to 600 million was raised for Medivation. As we hit inflection points, we will need to raise a dramatic amount of money."

Bailey, the CEO of Juvenescence, was one of the early backers of Medivation, where he was a board director for 7 years - before Pfizer stepped in to buy the biotech for 14 billion. The primary game plan at Juvenescence is to come up with various operations engaged in developing new anti-aging drugs. Juvenescence AI is a joint venture they've just set up with Alex Zhavoronkov, who runs Insilico Medicine. Mellon met Zhavoronkov while he was researching his book, and believes that the tech the scientist developed can illuminate new programs with a better chance of success. "They are going to take up to 5 molecules from us every year for development," says Zhavoronkov, an enthusiastic advocate of AI in drug research who's also been working on some alliances with big pharma players. The group has invested about 7 million in the technology so far getting the joint venture set up. More will follow.

Aside from the cellular pathways that have attracted their attention, the biotech will look to effect change in the mitochondria, the cell's powerhouse, as well as clean up senescent cells that accumulate as the body grows older. And Bailey expects he'll be working some Biohaven-like deals to develop an advanced pipeline at a rapid pace. The principals chipped in the seed millions for the company and invested in the joint venture with Zhavoronkov. Bailey says you can expect to see 20 million to 50 million more in funding from a friends-and-family raise before the end of the year. And it's expected to grow from there.

Zebrafish embryos have for the first time been frozen, thawed, and brought back to life. Researchers have been working on cryopreservation of zebrafish embryos for decades. It's never been done before. Over the past 60 years, scientists have had success preserving the sex cells and embryos of humans, cattle, mice, and many other animals. Trying to freeze and thaw fish embryos, however, has been more difficult because of their size and structure. The embryos are relatively large, bigger than a human egg. Fish embryos also have different compartments that freeze and thaw at different speeds. That can lead to the development of ice particles, which can damage the embryo.

Building on work by other scientists, researchers tweaked an existing cryopreservation method by injecting gold nanoparticles into zebrafish embryos, along with a cryoprotectant. The team froze the embryos in about one second using liquid nitrogen, then, after a few minutes, warmed them using a laser. The gold nanoparticles, which were distributed evenly throughout the embryos, absorbed the laser light and turned it into heat. The laser, which shown on the embryos for a millisecond, warmed developing fish so rapidly that they may have avoided being damaged by ice formation or other untoward effects of the quick-chill and thaw technique.

In the trials, only about 10 percent of the embryos survived to 24 hours. At this point, survivors started squirming and wiggling as their hearts, eyes, and nervous systems developed, proving their viability, yet none survived to day five, the final time point the team used. The advance is important for the field of genetics. Zebrafish have become an important model organism for studying the genetics of vertebrates and humans. Being able to preserve the different genetic lines of zebrafish generated in these studies means researchers wouldn't need to maintain live populations or run the risk losing irreplaceable research lines. It is also the most cost-effective method for this kind of research. The team is continuing to work on the technique to improve the viability of the embryos. Tweaks to the laser, gold nanoparticles, and even the cryoprotectant could make the method more suitable for embryos with a diameter of a millimeter or smaller. That would mean there would be one way of cryopreservation for all organisms with embryos of that size.

Cells in the body or in cultures eventually stop replicating. This phenomenon is called "senescence" and is triggered by shortening of telomeres, oxidative stress or genetic damage to the cells, either acute or simply due to the cell growing "old". Understanding the causes and impact of senescence can give us deep insights into the development of cancer and ageing. When cells senesce, they undergo profound changes, including the secretion of several inflammation-mediating proteins (cytokines, chemokines, extracellular-matrix proteins, growth factors). The production of this "senescence-associated secretory phenotype" controls a number of biological processes such as wound healing and tissue repair, but also tumor formation and some age-related disorders. But although we know how senescence increases the activity of the genes for these proteins, we know very little about how the entire process begins in the first place.

Researchers have now found that senescing cells use a mechanism of the innate immune system to regulate the secretion of inflammation-mediating molecules. The innate immune system includes fast-acting but non-specialized cells (macrophages, neutrophils, mast cells, etc.) that provide the first line of defense against the millions of potential pathogens to which humans are constantly exposed. The innate immune cells use a host of pattern recognition receptors to sense and identify foreign parts of an invading pathogen, such as the DNA of a virus. DNA-sensing is accomplished through a two-receptor system comprising an enzyme called cGAS and an adaptor molecule called STING. Once activated, the cGAS-STING pathway triggers the production of inflammatory proteins that help fight off the pathogen.

Unexpectedly, the researchers now found that senescent cells in the body use the cGAS-STING pathway to regulate and facilitate their secretion of inflammation mediators. But in the context of senescent cells, it is the cell's own DNA that activates cGAS because of defects in the integrity of the nuclear envelope. Examining the relevance of this fundamental mechanism, the study found that the cGAS-controlled secretion of cytokines appears to play a role in various contexts of senescence such oxidative stress, oncogene signaling, and irradiation. The scientists also observed that at least irradiation and oncogene activation exert these actions through cGAS-STING in vivo as well. The study shows that DNA sensing through the cGAS-STING pathway is an important regulator of senescence and the release of inflammatory mediators, and could also serve as surveillance system that protects the organism against neoplastic cells, which opens up new insights for our understanding of the development of cancer. Moreover, since the inflammatory response of senescent cells also promotes ageing, the cGAS-STING pathway could serve as new drug target to tackle age-related diseases.

Aging of the immune system, which is known as immunosenescence, involves a striking rearrangement of almost every component, leading to changes including enhanced as well as diminished functions. In addition, the functioning of the immune system has been demonstrated to be an excellent marker of health, given that several age-related changes in immune functions are predictive of mortality and lifespan. Thus, long-lived individuals seem to exhibit a high degree of preservation of several functions of the immune system with values similar to those observed in adult individuals. This may be essential to reach a very advanced age in a healthy condition.

Among all the age-related changes that the immune system undergoes, the most obvious is the involution of the thymus gland. Accordingly, one of the most marked age-related alterations in the immune cells has been reported in the T lymphocytes, specifically in the lymphoproliferative response to mitogens, which is decreased in old subjects for both humans and experimental animals. The study of the proliferative response of leukocytes to a given stimulus has become an important issue given that a low lymphoproliferative response to mitogens has been linked to an increased mortality, and together with other parameters, defines the immune risk phenotype in humans.

Cytokines are principal mediators of interactions among immune cells. They are responsible for the development and resolution of immune response and are greatly affected by the aging process. In fact, an age-related loss of homeostasis in cytokine networks can contribute significantly to health impairment in old age. In this context, together with the previously mentioned age-related loss of functionality in immune cells, aging is characterized by a chronic low-grade inflammatory status, so-called "inflammaging". Thus, it has been described that an age-related increase in release of pro-inflammatory cytokines in resting cells leads to a sterile inflammation. This is accompanied by an elevation of circulating levels of cytokines in old subjects, such as IL-6, which in addition has been related to a higher risk of mortality. However, cells from old subjects produce lower pro-inflammatory cytokines when needed to do so, i.e., after a mitogenic stimulus, compared to those of adult subjects. Again, long-lived individuals, despite having high levels of pro-inflammatory markers, have a postponed disease onset, making it difficult to understand whether "inflammaging" is beneficial or detrimental.

Based on the striking facts regarding lymphoproliferation and cytokine release by immune cells in long-lived individuals, it was hypothesized that these individuals could present different proliferative as well as cytokine release dynamics as an adaptive mechanism. Moreover, given that all the studies in long-lived individuals previously mentioned have been cross-sectional, it is still not known if they reach those advanced ages due to the maintenance of optimal immune cell function during their whole life (as if they were adults) or whether they experience an age-related impairment in these functions but are able to compensate for it. In order to address these questions, an individualized longitudinal study was performed on female ICR-CD1 mice analyzing the proliferation as well as the cytokine secretion profile of leukocytes obtained from animals at different ages. The study was performed starting at the adult age, 40 weeks old, and followed each animal individually until its death.

In the present study, it has been found that old mice exhibit a significant increase in the basal proliferation of immune cells, what takes place in the absence of a proliferative stimulus, with respect to when they were younger. In contrast, long-lived mice show basal proliferative levels similar to when they were adults. The high proliferation in the absence of stimulus seen in old mice implies a deregulation of the immune system. Those mice that naturally achieve high longevity are the ones that not only maintained lower levels of basal proliferation and higher levels of proliferation after stimulation during their whole lifetime, but are also those that achieve a better control of the effects of aging on the immune functions. Thus, long-lived mice are those that maintained a lower secretion of pro-inflammatory cytokines and a higher secretion of anti-inflammatory cytokines in unstimulated conditions as well as a higher one upon stimulation when they were old, compared to their age-matched counterparts. This is the first study to demonstrate that the animals reaching high longevity experience immune-senescent changes (to a lesser extent than those which do not reach advanced ages), but they are able to compensate for them by showing optimal levels when they are long-lived.

Until recent years, a basic assumption in biology was that mutations in the DNA sequence were the only source of heritable phenotypic variation. It is commonly believed that genetic information may be transmitted to the next generations by germ cells only, while somatic cells do not have any inheritance function. The core of this theory is the idea that information is not capable of being transferred from somatic to germline cells and, respectively, to the next generations. This concept is commonly referred to as the Weismann's barrier. According to this concept, a strict distinction exists between innate and acquired characters. There is, however, significant empirical evidence to suggest that the Weismann's barrier is not entirely impermeable and can be crossed.

Examples for non-DNA sequence-based inheritance across generations have been obtained in a variety of species, including microbes, plants, worms, flies, fish, rodents, pigs, and humans. Many recent papers highlight the role of epigenetic mechanisms in mediating these effects. These processes include modified patterns of DNA methylation and histone posttranslational modifications, replacement of canonical histones with histone variants, as well as altered noncoding RNA expression causing changed local accessibility to the genetic material and modified gene expression. In several recent studies, the potential importance of non-genomic transgenerational effects in the inheritance of age-related characteristics has been highlighted. However, the transgenerational effects on longevity have been reported only rarely to date. Most of the papers reviewing and discussing such effects are focused solely on data obtained from the nematode Caenorabditis elegans, although similar findings were obtained in other species as well.

In evolutionary terms, the transmission of the adaptive transcriptional patterns acquired throughout the parental life course in subsequent generations via the mechanism of epigenetic memory can enable the organism to better survive in potentially adverse environments. In particular, it has been repeatedly reported that offspring of parents exposed to nutritional stresses exhibit altered expression of genes related to metabolic functions including those implicated in pro-longevity metabolic pathways. The mechanisms potentially responsible for such inter- and transgenerational effects are currently the subject of active investigation. In most studies on short-lived models such as nematodes and flies, the role of histone modifications in transgenerational transmission of epigenetic information was highlighted, while in rodent models changes in DNA methylation have been mainly detected.

Researchers have discovered tell-tale signs of Alzheimer's disease in 20 elderly chimpanzee brains, rekindling a decades-old debate over whether humans are the only species that develop the debilitating condition. Whether chimps actually succumb to Alzheimer's or are immune from symptoms despite having the key brain abnormalities is not clear. But either way, the work suggests that chimps could help scientists better understand the disease and how to fight it - if they could get permission to do such studies on these now-endangered animals.

A definitive diagnosis of Alzheimer's includes dementia and two distortions in the brain: amyloid plaques, sticky accumulations of misfolded pieces of protein known as amyloid beta peptides; and neurofibrillary tangles, formed when proteins called tau clump into long filaments that twist around each other like ribbons. Many other primates including rhesus monkeys, baboons, and gorillas also acquire plaques with aging, but tau tangles are either absent in those species or don't fully resemble those seen in humans. In the new study, and thanks to a newly founded center that collects brains from chimps that die at zoos or research centers, the team was able to examine the brains of 20 chimps aged 37 to 62 - the oldest recorded age for a chimp, roughly equivalent to a human at the age of 120. Of these chimps, 13 had amyloid plaques, and four also had the neurofibrillary tangles typical of more advanced stages of Alzheimer's in humans.

But so far, only humans are known to show the Alzheimer's trifecta of plaques, tangles, and dementia. The 20 chimps whose brains were studied had not been tested for cognitive or behavioral changes. As a result, "we can't say these chimps had Alzheimer's, but we can say for sure that they are the only other species with its pathologic hallmarks." Some scientists aren't persuaded that the chimp brains really do match those of human Alzheimer's patients. In human brains, amyloid plaques are associated with neuron death, which wasn't measured in the new study. The researchers plan to go back to the same chimp brains to calculate neuron death, but proving that chimps develop dementia will require research on living animals.

Scientists have revealed, for the first time, a method to reprogram specific T cells. More precisely, they discovered how to turn pro-inflammatory cells that boost the immune system into anti-inflammatory cells that suppress it, and vice versa. The researchers studied two types of cells called effector T cells, which activate the immune system to defend our body against different pathogens, and regulatory T cells, which help control the immune system and prevent it from attacking healthy parts of its environment.

By drawing on their expertise in drug discovery, the team identified a small-molecule drug that can successfully reprogram effector T cells into regulatory T cells. Their study describes in detail a metabolic mechanism that helps convert one cell type into another. This new approach to reprogram T cells could have several medical applications. For instance, in autoimmune disease, effector T cells are overly activated and cause damage to body­­. Converting these cells into regulatory T cells could help reduce the hyperactivity and return balance to the immune system, thus treating the root of the disease. In addition, the study could improve therapies using stem cells. At least in theory, producing regulatory T cells could promote immune tolerance and prevent the body from rejecting newly-transplanted cells.

"Our work could also contribute to ongoing efforts in immunotherapy for the treatment of cancer. This type of therapy doesn't target the cancer directly, but rather works on activating the immune system so it can recognize cancer cells and attack them." Many cancers take control of regulatory T cells to suppress the immune system, creating an environment where tumors can grow without being detected. In such cases, the team's findings could be used to transform regulatory T cells into effector T cells to strengthen the immune system so it can better recognize and destroy cancer cells.

AgeX Therapeutics, Inc. is a biotechnology company formed in 2017 as a subsidiary of BioTime, Inc. Its mission is to apply technology related to cell immortality and pluripotency to human aging and age-related disease. The Company's technology platform has three facets: Pluripotent stem cell-derived progenitor cell lines representing over 200 types of cells in the body (PureStem technology); HyStem matrices; and induced tissue regeneration (iTR) - the latter being an emerging technology directed at inducing the immortal regeneration of tissues in the body. ​

Through BioTime, AgeX has license to a large consolidated technology and patent estate including technologies invented at Geron and subsequent companies. AgeX is leading off with cell-based regenerative therapeutics for significant unmet needs in age-related disease such as type II diabetes and ischemic disease. In addition, it will also be advancing products based on an entirely new technology platform aimed at the central molecular processes of aging itself designated "induced Tissue Regeneration (iTR)." AgeX scientists believe that the combination of telomerase therapy and iTR may unlock the potential of immortal tissue regeneration in humans.

Some naturally-occurring animals such as the Mexican salamander can profoundly regenerate damaged tissues. Humans also have this potential, but only in the first weeks of development. Using advanced molecular and artificial intelligence technologies, we have identified pathways we believe may provide means of unlocking this profound biology in human medicine. The pathways suggest that they may also be integral to the biology of aging and cancer as well. Patents relating to this emerging technology have been filed and animal studies are currently underway. The combination of pluripotent stem cell and iTR technology may provide AgeX with a valuable platform to address large markets associated with chronic degenerative age-related disease.

Promising research points towards a possible stem cell treatment for several lung conditions, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis. These diseases of the lung involve the buildup of fibrous, scar-like tissue, typically due to chronic lung inflammation. As this fibrous tissue replaces working lung tissue, the lungs become less able to transfer oxygen to the blood. In the case of IPF, which has been linked to smoking, most patients live for fewer than five years after diagnosis. The two drug treatments for IPF reduce symptoms but do not stop the underlying disease process. The only effective treatment is a lung transplant, which carries a high mortality risk and involves the long-term use of immunosuppressive drugs.

Scientists have been studying the alternative possibility of using stem cells to treat IPF and other lung fibrosis diseases. Some types of stem cells have anti-inflammatory and anti-fibrosis properties that make them particularly attractive as potential treatments for fibrotic diseases. Researchers have focused on a set of stem cells and support cells that reside in the lungs and can be reliably cultured from biopsied lung tissue. The cells are called lung spheroid cells for the distinctive sphere-like structures they form in culture. Lung spheroid cells showed powerful regenerative properties when applied to a mouse model of lung fibrosis. In their therapeutic activity, these cells also outperformed other non-lung-derived stem cells known as mesenchymal stem cells, which are also under investigation to treat fibrosis.

Researchers showed that they could obtain lung spheroid cells from human lung disease patients with a relatively non-invasive procedure called a transbronchial biopsy. They cultured lung spheroid cells from these tiny tissue samples until they were numerous enough - in the tens of millions - to be delivered therapeutically. When they infused the cells intravenously into mice, they found that most of the cells gathered in the animals' lungs. The researchers then induced a lung fibrosis condition in rats that closely resembled human IPF. Then the researchers injected the new cultured spheroid cells into one group of rats. Upon studying this group of animals and another group treated with a placebo, the researchers saw healthier overall lung cells and significantly less lung inflammation and fibrosis in the rats treated with lung spheroid cells.

In the last year or so we have seen remarkable progress with a number of interventions that target the aging processes to prevent and treat age-related diseases. There is plenty to be excited about, and with all this good news recently it is tempting to become overly optimistic. I have seen a significant number of people suggest that everything will be fine now, because the first technologies are starting to arrive in the repair based approach to aging, but this is a dangerous mindset to fall into. We should not think we are close to bringing the aging processes under medical control. The metabolism of the human body is a highly complex interconnected machine and anyone with an understanding of biology understands that controlling this complexity is likely the work of decades if not longer. However, there is an approach that seeks to sidestep this complexity - rejuvenation biotechnology.

Rejuvenation biotechnology is a multi-disciplinary field of science whose aim is the prevention and reversal of age-related diseases by targeting the aging processes that cause them. This is a dramatic deviation from traditional medicine and in particular geriatrics which aims to treat the consequences, often by attempting to tweak metabolism far downstream from the actual root causes, rather than prevent it happening in the first place by focusing on where the damage begins. This traditional approach of treating the symptoms and not the cause is an approach doomed to fail, and considering people continue to die from age-related diseases it is time to admit that this approach has been a spectacular failure. Repairing the underlying damage, whilst itself not trivial, is considerably less complex than attempting to tweak metabolism or treating the consequences as traditional geriatrics does. Regardless of how you categorize the damages of aging, be it the seven damages model of SENS or the Hallmarks of Aging model, they are much the same and both advocate the repair approach to aging. The damage repair approach is becoming a realistic goal in the next couple of decades and that is very good news indeed.

Some parts of the damage repair approach are now far advanced and enjoying a great deal of attention and hype in the media. But there are a number of approaches to damage that are yet to reach this level of attention. Because aging comprises of a number of interlinked but distinct processes, addressing only one or two of them is unlikely to yield significant increases in healthy lifespan. This is confirmed in rodent experiments where a single damage has been addressed. We see increased lifespans as a result of addressing these hallmarks of aging and a delay of age-related diseases, which is the aim of rejuvenation biotechnology. And yet, these animals ultimately still die of the age-related damages that are not being addressed. Believing that addressing just one form of damage will make a dramatic difference puts us in serious danger of becoming overly optimistic and thus complacent. Quite simply, there are no magic bullets.

At the risk of stating the completely obvious: we should be focusing the greatest efforts now on the areas where progress is the least advanced. We need to help these approaches that are lagging behind catch up with the rest that are more advanced. Areas like crosslink breaking, mitochondrial gene transfer and the destruction of misfolded proteins are all areas that are in need of support. As it stands these and other critical research areas that are needed to realize full medical control of the aging processes to address age-related diseases are yet to reach a proof-of-concept stage. That leaves the basic science and early-stage development of these technologies entirely in the hands of philanthropy.