"Why do we age?"; "Can we intervene in the aging process?"; and if so, what approaches should aging science take to transform research into viable therapeutic interventions to improve public health? Understanding the mechanisms of aging will be of vital importance to answering these questions. However, several obstacles stand in the way of generating efficacious and safe interventions that extend the period of healthy life. At the 5th Annual Aging and Drug Discovery Forum which was held during the Basel Life Congress, Basel, Switzerland, September 12-13, 2018, leading aging experts from academia and industry came together to discuss top issues in aging research. Here, we provide a brief overview of the presented results and discussion points.

The International Society on Aging and Disease (ISOAD) recently held its third international conference in Nice, France, bringing together researchers - and longevity activists - from around the world. Prof. Gilson founded the Ircan Institute for Research on Cancer and Aging in Nice in 2012. "It was perhaps the first institute that specifically aimed to couple the themes of aging and cancer in the same laboratory, even if the links between them had been known to some extent. That was its originality. We've laid the foundations - to have the expertise, the right people, the right models - and I think we're going to have important answers for the role of telomeres in aging and, more generally, cellular senescence, which is the favorite current target of a lot of pharmaceutical or fundamental research that we are revisiting via our original models."

When I first learned about the possibility of achieving human rejuvenation through biotechnological means, little did I know that this would lead me to meet many of the central figures in the field during a conference some seven years later - let alone that I would be speaking at the very same event. Yet, I've had the privilege to attend the Fourth Eurosymposium on Healthy Ageing (EHA) held in Brussels on November 8-10, an experience that gave me a feel of just how real the prospect of human rejuvenation is. The first day of the conference was basically a journey into the world of cellular senescence: methods of targeting senescent cells, the SASP, drug delivery systems, and so forth; however, other topics, such as the extracellular matrix, transcriptomics, and stem cells, were also discussed. A great deal more researchers and other people otherwise involved in the community were present on the first morning than there were at the pre-conference meeting; the peak was probably during the second day, which saw a wider variety of topics, including genomics, DNA repair, bioinformatics, and the first panel of the conference.

Dr. Joao Pedro de Magalhaes, Biologist at the University of Liverpool and coordinator of the UK Cryonics and Cryopreservation Research Network

I'd say that with today's technology, cryonics severely damages the body's cells. Even under optimal conditions (i.e., the procedure starts right after death), there are several problems in cryonics. In particular, cryoprotectant agents have toxic effects on human tissues with prolonged exposure. Vitrifying large organs like the brain can also result in fractures due to different cooling rates in different parts. Under non-optimal conditions (i.e., if a significant time elapses between death and being cryopreserved) much more damage can occur because cells start to die, and brain cells in particular start to die within minutes after cardiac arrest, due to lack of nutrients and oxygen (called ischemia). Therefore, it will take huge scientific advances in areas like tissue engineering and regenerative medicine to make cryopreserved individuals alive and healthy again. As such, I would say that the chances of cryopreserved individuals ever be revived is low but not impossible. And then the argument is that the worse possible outcome of being cryopreserved is to remain dead, so cryonics gives you a chance of future revival that will not happen if you are buried or cremated.

Mark Kline, Co-Founder and CTO, X-Therma Inc., a company improving cold storage of stem cells, tissues, and whole organs

The hardest thing to solve is: how do you freeze things without damaging them? You mix in all these cryoprotectants - like antifreeze for your car, but geared towards biology - in an effort to prevent ice formation within the cells and tissues. But you need to drastically lower the temperature - down to about -196 degrees C, liquid nitrogen temperature. Preventing ice formation at that temperature, throughout a very large tissue, is very, very difficult. So there's the chemistry problem (preventing ice), the biology problem (tissue damage, connection damage), the physics problem (how do you evenly cool something as large as an organ? And how do you warm it up evenly afterwards, without damaging it?). I think there are much more imminent applications for cryopreservation, like organ preservation. Preserving organs has a high-value impact for the medical system, and also is much more feasible than preserving a whole body. You can save many, many lives with organ preservation.

Nick Bostrom, Professor at the University of Oxford and Director at the Future of Humanity Institute and the Governance of AI program

Technically it seems like it should probably work. The freezing (rather: vitrification or plastination) and storing we can do now. The bringing back part may however require the assistance of machine superintelligence in order to repair the extensive cellular damage that occurs during the suspension process.

Dennis Kowalski, President, Cryonics Institute

The scientifically correct answer is that we do not know, since no one knows the future and what will be possible. However, that is why some people have signed up to preserve their bodies at liquid nitrogen temperatures in hopes that future technology and medicine will be able to answer that very question. New technologies moving forward might mean advanced, AI-guided stem cell therapies that regenerate tissues that have been damaged by aging, freezing, or death itself. Technologically we are advancing at an exponential pace, and this means that things considered impossible even a few decades ago will become reality.

Cathal O'Connell, Researcher in 3D bioprinting and biofabrication at BioFab3D, St Vincent's Hospital, Melbourne

All signs point to no. The freezing-down process is critical. Doing this in a way that preserves cell function - especially regarding connectivity in the human brain - is way beyond our current capabilities. Unfortunately, everyone who has ever been frozen so far is essentially turned to mush. These people will never be revived. Cryonics in its current form is more of a religion than a science. Rather than a divine entity, its followers place their faith in technological progress. The ability of some organisms to survive freezing is a sign from nature that what cryonics promises might one day be possible. But getting there will require a massive investment - billions in funding, thousands of scientists, decades of research. Without a clear economic incentive, that investment is not forthcoming. As my old professor says, a vision without funding is hallucination.

Ralph Merkle, Director of Alcor Life Extension Foundation, the world's leading cryonics organization

The short version is: many of the patients at Alcor will likely be revived sometime this century. Had you asked a random person in 1940 if flight to the moon was possible, you'd likely have been told "no." If asked why, a typical answer was "because there's no air to push against in space." This scientific-sounding but totally false objection was infamous among knowledgeable scientists, and was the basis for the New York Times' 1920 editorial denouncing Robert Goddard. Yet those knowledgeable about space flight had been forecasting flight to the moon for decades before the event. Similarly, those knowledgeable about nanomedicine have also been forecasting the revival of cryopreserved patients for decades, and those forecasts are likewise based on a sound assessment of physical law. Until the structures in the brain that encode our memories and personality have been so obliterated that they cannot in principle be inferred and restored to a functional state, you are not dead. This information theoretic criterion of death is obviously much more difficult to meet than current legal or medical definitions, hence the belief that cryopreserved patients are not actually dead.

Michael Hendricks, Canada Research Chair in Neurobiology and Behaviour and Assistant Professor of Biology at McGill University and wrote "The False Science of Cryogenics" for the MIT Technology Review

If you mean people who have already had their brains, heads, or bodies cryogenically stored after death (or are doing so with current technology): no, they will never be revived. They are dead, and will remain dead forever. Will it ever be possible to store a dead person (or a dead person's brain) in such a way that they can be revived? Almost certainly not. Look at the world. The only good thing we still reliably do for future generations is get out of their way. Let's not take that away from them too... they will have their hands full with all the horrific problems we've left them because of our selfishness and greed. We shouldn't making them responsible for keeping our bodies cold, too.

Human cytomegalovirus is a leading cause of birth defects and transplant failures. As it's evolved over time, this virus from the herpes family has found a way to bypass the body's defense mechanisms that usually guards against viral infections. Until now, scientists couldn't understand how it manages to do so. Normally, when a virus enters your cell, that cell blocks the virus's DNA and prevents it from performing any actions. The virus must overcome this barrier to effectively multiply. To get around this obstacle, cytomegalovirus doesn't simply inject its own DNA into a human cell. Instead, it carries its viral DNA into the cell along with proteins called PP71. After entering the cell, it releases these PP71 proteins, which enables the viral DNA to replicate and the infection to spread.

"The way the virus operates is pretty cool, but it also presents a problem we couldn't solve. The PP71 proteins are needed for the virus to replicate. But they actually die after a few hours, while it takes days to create new virus. So how can the virus successfully multiply even after these proteins are gone?" The researchers found that, while PP71 is still present in the cell, it activates another protein known as IE1. This happens within the first few hours of the virus entering the cell, allowing the IE1 protein to take over after PP71 dies and continue creating new virus. To confirm their findings, the team created a synthetic version of the virus that allowed them to adjust the levels of the IE1 proteins using small molecules.

"We noticed that when the IE1 protein degrades slowly, as it normally does, the virus can replicate very efficiently. But if the protein breaks down faster, the virus can't multiply as well. So, we confirmed that the virus needs the IE1 protein to successfully replicate." The new study could lead to a new therapeutic target to attack cytomegalovirus and other herpesviruses.

A fundamental signal-processing problem is how biological systems maintain phenotypic states (i.e., canalization) long after degradation of initial catalyst signals. For example, to efficiently replicate, herpesviruses (e.g., human cytomegalovirus, HCMV) rapidly counteract cell-mediated silencing using transactivators packaged in the tegument of the infecting virion particle. However, the activity of these tegument transactivators is inherently transient - they undergo immediate proteolysis but delayed synthesis - and how transient activation sustains lytic viral gene expression despite cell-mediated silencing is unclear.

Using an HCMV mutant, we find that positive feedback in HCMV's immediate-early 1 (IE1) protein is of sufficient strength to sustain HCMV lytic expression. Single-cell time-lapse imaging and mathematical modeling show that IE1 positive feedback converts transient transactivation signals from tegument pp71 proteins into sustained lytic expression, which is obligate for efficient viral replication, whereas attenuating feedback decreases fitness by promoting a reversible silenced state. Together, these results identify a regulatory mechanism enabling herpesviruses to sustain expression despite transient activation signals - akin to early electronic transistors - and expose a potential target for therapeutic intervention.

Researchers looked for overall differences between old and young T cells. They isolated T cells from the spleens of young and old mice and noticed that, in general, older mice had fewer T cells. Next, to gauge the cells' immune fitness, the researchers activated the T cells by mimicking signals normally turned on by pathogens during infection. The older T cells showed diminished activation and overall function in response to these alarm signals. Specifically, they grew more slowly, secreted fewer immune-signaling molecules and died at a much faster rate than young T cells. The researchers also observed that aged T cells had lower metabolism, consumed less oxygen and broke down sugars less efficiently. They also had smaller than normal mitochondria, the cells' power-generators that keep them alive

To pinpoint the metabolic pathways behind this malfunction, the scientists analyzed all the different proteins in the cells, including those that might be important for coaxing a T cell from dormancy into a fighting state. The team found that the levels of some 150 proteins were lower-than-normal upon activation of the aged T cells, compared with young T cells. About 40 proteins showed higher than normal levels in aged versus young T cells. Many of these proteins have unknown functions, but the researchers found that proteins involved a specific type of metabolism, called one-carbon metabolism, were reduced by nearly 35 percent in aged T cells.

One-carbon metabolism comprises a set of chemical reactions that take place in the cell's mitochondria and the cell cytosol to produce amino acids and nucleotides, the building blocks of proteins and DNA. This process is critical for cellular replication because it supplies the biologic material for building new cells. The team's previous work had shown that one-carbon metabolism plays a central role in supplying essential biological building blocks for the growing army of T cells during infection. So, the scientists wondered, could adding the products of this pathway to weakened T cells restore their fitness and function?

To test this hypothesis, the team added two molecules - formate and glycine, the main products of one-carbon metabolism - whose levels were markedly reduced in aged T cells. Indeed, adding the molecules boosted T cell proliferation and reduced cell death to normal levels. The researchers caution that while encouraging, the effects were observed solely in mouse cells in lab dishes rather than in animals and must be confirmed in further experiments.

T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation.

We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.

Even though humans can give their hearts to compatible persons with little more than a side of immunosuppressants, cross-species transplantation is not so straightforward. More than 60 percent of attempts to replace a baboon's heart with that of a pig ended in the recipients dying within two days. Two important developments pumped hope into the field over the past few years. First, researchers began using the gene-editing tool CRISPR-Cas9 to remove parts of the pig genome that might harm humans or provoke an immune response. Then in 2016 researchers took this further by showing baboons could survive with a genetically engineered pig heart implanted into their abdomens for nearly 1,000 days - if the baboon was on a certain cocktail of immunosuppressants.

For the new work researchers wanted to see if the same genetically engineered pig hearts and immunosuppressant regime could support the life of a baboon. But the first five animals in the new study did not live long. Three died of heart failure almost immediately. It turns out porcine hearts are more vulnerable compared to human hearts. During the period between removal from a pig and implantation into a baboon the heart will sustain damage similar to that caused by a heart attack. Human hearts can often recover from this damage, but the pig hearts could not.

So researchers tried something new with another group of baboons and repeatedly immersed the pig hearts in an experimental nutrient solution for a couple of hours. The researchers think this formulation, originally designed to help transport human hearts long distances, might have helped keep the pig hearts from deteriorating too much. These baboons hung on for about a month before dying - this time because the pig hearts began swelling inside the monkeys' chests, eventually squeezing against the rib cages and failing. "A pig grows to maturity within four months or so, but a baboon takes about 10 years to grow. So the pig heart was growing in the primate as if it was still in a pig. We were just astonished. Nobody had experienced this before - the heart grew like a tumor."

In the third group of baboons researchers added an immunosuppressant drug called temsirolimus, which could also stop the pig hearts' unwanted growth. With the exception of one baboon that died of mechanical heart failure 51 days after surgery, the transplant recipients in this group survived in good health until the researchers euthanized them at 90 or 180 days, an action required under the study protocol approved by officials. The study is invigorating xenotransplantation researchers who, after decades of sometimes dismal attempts, say human trials are finally in sight.

Geroscience is a multidisciplinary field that examines the relationship between biological aging and age-related diseases. The Trans-NIH Geroscience Interest Group Summit discussed 7 processes that contribute to biological aging: macromolecular damage, epigenetic changes, inflammation, adaptation to stress, and impairments in proteostasis, stem cell regeneration, and metabolism. Intriguingly, these 7 processes are highly intertwined with one another. Thus, targeting the common biological processes of aging may be an effective approach to developing therapies to prevent or delay age-related diseases.

Biological aging is the leading risk factor for the major debilitating chronic diseases of old age that cause morbidity and mortality, including Alzheimer's disease (AD) and other dementias. Drugs that treat fundamental biological mechanisms of aging have been proposed to be useful for most prevalent chronic diseases of aging. In fact, many repurposed drugs are used to treat other age-related diseases. Despite over 75 years of accumulated research on biological aging, the current drug development pipeline is dominated by therapeutics targeting amyloid-β and tau, and there has been proportionately less translation of biological gerontology into our efforts to develop drugs for AD.

Nevertheless, aging biology provides numerous novel targets for new drug development for AD. Because of the multifaceted nature of biological aging, it is unlikely that drugs addressing a single target will be very successful in effectively treating AD. Nevertheless, single drug clinical trials may be needed to demonstrate incremental benefits, even if modest, before combination trials can be pursued. As interventions that target one aberrant system tend to also attenuate others, ultimately, combination therapies that target multiple age-related dysfunctions may produce synergistic activities.

Combination therapies are already the standard of care for other diseases of aging, including heart disease, cancers, and hypertension, and will likely be necessary in treating AD and other dementias. And because the same biological aging mechanisms underpin the common diseases of aging, repurposing drugs already on the market is a rational strategy for testing new therapies for AD and related dementias, including the sporadic forms of frontotemporal dementia and vascular dementia. Novel therapeutics for new and relevant targets will clearly also be needed.

In addition to combination therapies, addressing the multifaceted nature of the relationship between biological aging and AD with drugs possessing pleiotropic effects (simultaneously producing more than one effect) will be advantageous. Many effective drugs act on multiple targets while single-targeted approaches seldom progress to the final stages of clinical trials. For example, statins are widely used to lower cholesterol levels in patients with dyslipidemia, but statins also have pleiotropic effects that are independent of their effects on cholesterol, including improved endothelial function, inhibition of vascular inflammation, stabilization of atherosclerotic plaques, and immunomodulation. To effectively treat AD, pleiotropic drugs may need to hit the right nodes of relevant biological networks affected by aging such that they positively influence those networks and interconnected pathways.

Finally, a parsimonious approach to drug discovery and development with regard to translating knowledge from biological aging to AD is needed. For example, due to the plethora of misfolded proteins that accumulate with aging in the brain, biologics that attempt to address a single misfolded protein may be far less efficacious than drugs that enhance autophagy and clearance of all misfolded proteins. Similarly, age-related inflammation, vascular disease, epigenetic dysregulation, mitochondrial/metabolic dysfunction, and synaptic failure may be upstream causes of neuronal dysfunction and death leading to the classic pathologic hallmarks that have been historically among the first drug targets in AD. A better understanding and translation of the systemic, cellular, and molecular processes of biological aging that precede and increase vulnerability to AD will help identify new strategies and therapeutic targets for drug discovery and development.

Vascular calcification is associated with physiological aging and is characterized by the deposition of calcium-phosphate crystals in the aortic media and/or intima, usually as hydroxyapatite, the main component of bone. Vascular calcification reduces aortic and arterial compliance and elastance, hampering cardiovascular system function. It is linked to poor clinical outcomes and contributes to cardiovascular morbidity and mortality. Because tissue mineralization may occur at normal concentrations of calcium and phosphate, regulatory mechanisms exist to limit this process to bone and cartilage. Several endogenous inhibitors of vascular calcification have been identified, including the matrix Gla protein, fetuin A, osteopontin, and pyrophosphate.

Pyrophosphate is a potent inhibitor of calcium-phosphate crystal formation and growth. Vascular tissue mineralization occurs when the synthesis of vascular calcification inhibitors is impaired or when the formation of calcium-phosphate crystals is enhanced, for example, by hyperphosphatemia, the main risk factor for vascular calcification. Despite findings showing that hyperphosphatemia triggers vascular calcification, the effects of hyperphosphatemia on extracellular pyrophosphate metabolism remain unclear. A recent study investigated pyrophosphate metabolism in the context of phosphate-induced vascular calcification. It was found that calcification is a passive process that can be actively prevented by pyrophosphate.

The main conclusion of this new study was that high phosphate concentrations resulted in the increased synthesis of pyrophosphate over time. Moreover, the hydrolysis of pyrophosphate was found to decrease during early stages, but increase during later stages, of hyperphosphatemia. Although overall pyrophosphate production is higher during hyperphosphatemia, it was not sufficient to block calcium-phosphate deposition. A growing body of evidence suggests that pyrophosphate is the predominant endogenous inhibitor of vascular calcification. The results of this study, along with previous findings, suggest that induction of pyrophosphate synthesis may be an easy and effective therapeutic strategy to inhibit vascular calcification associated with aging and other pathological conditions.

Our DNA is organised into chromosomes in all the cells in our bodies. At the end of each chromosome is a repetitive DNA sequence, called a telomere, that caps the chromosome and protects its ends from deteriorating. As we grow older, the telomeres shorten and this is an important molecular mechanism for cell aging, which eventually leads to cell death when the telomere are no longer able to protect the chromosomal DNA. The process of telomere shortening is regulated by several proteins. Among them is the enzyme telomerase that is able to counteract the shortening process and can even add length to the telomeres.

Researchers enrolled 266 young, healthy but previously inactive volunteers and randomised them to six months of endurance training (continuous running), high intensity interval training (warm-up, followed by four bouts of high intensity running alternating with slower running, and then a final cool down of slower running), resistance training (circuit training on eight machines, including back extension, crunch, pulldown, seated rowing, seated leg curl and extension, seated chest press and lying leg press), or to an unchanged lifestyle (the control group).

The participants who were randomised to the three forms of exercise undertook three 45-minutes sessions a week, and a total of 124 completed the study. The researchers analysed telomere length and telomerase activity in white blood cells in blood taken from the volunteers at the start of the study, and two to seven days after the final bout of exercise six months later. Telomerase activity was increased two- to three-fold and telomere length was increased significantly in the endurance and high intensity training groups compared to the resistance and control groups.

Previous research has shown that longer telomeres and increased telomerase activity are associated with healthy aging. However, this is the first prospective, randomised controlled study of the effects of different forms of exercise on these two measurements of cellular aging. A possible mechanism that might explain why endurance and high intensity training could increase telomere length and telomerase activity is that these types of exercise affect levels of nitric oxide in the blood vessels, contributing to the changes in the cells.

Neurons in the central nervous system - the brain and spinal cord - and the peripheral nervous system are very similar except in their ability to regenerate. Researchers realized that studying peripheral neurons could help us understand why some damaged neurons regenerate and others do not. They turned to a unique kind of sensory cell that spans both nervous systems. Known as dorsal root ganglion neurons, these cells have long tendrils, called axons, with two offshoots. One branch of the axon connects to cells in the body's periphery and can regenerate if cut; the other side links up with cells in the spinal cord and cannot regrow after injury.

The researchers grew mouse dorsal root ganglion neurons in the lab and then cut them to find out what biological processes occur as the cells regrow their axons. They also cut the sciatic nerve - which runs up the leg and into the spinal cord through the dorsal root ganglia - in mice. The researchers then identified a suite of genes needed to be turned off for the axons to regenerate. "Other people also have shown that a big swath of genes is turned down during regeneration, but as a field we've just said, 'Eh' and ignored them to focus on the genes that are activated. Here, we showed that establishing a regeneration program means some genes have to be turned on but a lot have to be turned off."

In particular, a set of genes related to sending and receiving chemical and electrical signals - the primary duty of mature neurons - had to be silenced for the injury to heal. "The injured neuron has to stop functioning as a neuron and focus on repairing itself. This means the neuron has to transition back to an immature state so it can re-engage developmental programs and regrow." The idea that cells must become less mature in order to regenerate is not new, but the study provides evidence in support of that idea. The researchers identified the key molecular and genetic players involved in regressing to a less mature state, and showed that the timing of the regression was crucial to successful recovery. They are now working on developing a more detailed understanding of when and for how long specific genes must be shut off, and whether silencing the genes in neurons from the central nervous system will induce them to regrow after injury.

Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson's disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker expression and reduction of M2 marker expression were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α.

Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated with Atg5 knockdown in cells, but alleviated given microglia pretreatment with rapamycin, suggesting that activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.

Parrots are one of the most distinct and intriguing groups of birds, with highly expanded brains, highly developed cognitive and vocal communication skills, and a long lifespan compared to other similar-sized birds. Yet the genetic basis of these traits remains largely unidentified. To address this question, we have generated a high-coverage, annotated assembly of the genome of the blue-fronted Amazon (Amazona aestiva) and carried out extensive comparative analyses with 30 other avian species, including 4 additional parrots.

We identified several genomic features unique to parrots, including parrot-specific novel genes and parrot-specific modifications to coding and regulatory sequences of existing genes. We also discovered genomic features under strong selection in parrots and other long-lived birds, including genes previously associated with lifespan determination as well as several hundred new candidate genes. These genes support a range of cellular functions, including telomerase activity; DNA damage repair; control of cell proliferation, cancer, and immunity; and anti-oxidative mechanisms.

We also identified brain-expressed, parrot-specific paralogs with known functions in neural development or vocal-learning brain circuits. Intriguingly, parrot-specific changes in conserved regulatory sequences were overwhelmingly associated with genes that are linked to cognitive abilities and have undergone similar selection in the human lineage, suggesting convergent evolution. These findings bring novel insights into the genetics and evolution of longevity and cognition, as well as provide novel targets for exploring the mechanistic basis of these traits.

Macrophages are white blood cells that live in organs and are key components of our immune system. They have a well-established ability to fight infections, but more recently, have been shown to help promote repair and regeneration of tissues. Researchers have found that instead of a single type of macrophage, there are at least four types that live within the uninjured heart, and that number increases to 11 after a heart attack, which indicates the immune system behaves in much more complex fashion than was imagined.

First, they found that neonatal-like macrophage cells are lost after a heart attack in adults, which could explain why the adult heart may not heal itself as well as the neonatal heart. In very young animals, neonatal macrophages increase in number and are very effective at triggering the regrowth of heart muscle and blood vessel cells. "Genetically removing neonatal-like macrophages at the time of the heart attack in adult animals worsens heart function most profoundly at the region of the heart separating injured and uninjured heart muscle - the only zone of the adult heart where they increase in number."

Researchers also found large numbers of macrophages are attracted to the heart after a heart attack, and a small number enter into the neonatal state, except, too late. By the time they arrive on site after a heart attack, a scar has formed in the heart in the place of heart muscle. "Each cell has a unique role to play in the human body, but our next question is: how can we guide a cell that enters the heart into a neonatal state more efficiently and, ultimately, more effectively?"

What are the most promising near-term therapies that may actually turn back the clock on biological aging?

Senolytic treatment, obviously, is the one that is here already and is presently available. It is fortunate that some of the first drugs identified to have this effect are, to a significant degree, already widely used and cheap. The animal results are far better in terms of robustness and reproducibility than any of the calorie restriction mimetic and other stress response tinkering work. The first human data from formal trials will arrive late this year or in early 2019. These first-generation approaches are killing only about half of the senescent cells at best (and far fewer than that in some tissues) but are nonetheless very effective in comparison to any other approach to age-related inflammatory disease.

The next approach to arrive that will likely have a similar character and size of effect is breaking of glucosepane cross-links, but since that involves a completely new enzyme-based therapy, we're unlikely to see it in people any sooner than a decade from now. If there is interest in that field, someone might uncover a useful small molecule prior to then, but it seems unlikely.

Other than that, over that same timeframe: (a) advances in stem cell medicine, moving beyond the simple transplantation therapies that do little other than suppress inflammation towards ways to actually replace damaged populations and have them get to work; (b) removal of amyloids through means other than the immunotherapies that are the present staple of that field; (c) forms of immune system restoration, such as via thymic regrowth, replacement or enhancement of hematopoietic stem cells, and clearance of problem immune cells.

I'm not convinced that there is an enormous benefit to be realized from approaches to enhance mitochondrial function, such as NAD+ precursors and mitochondrially targeted antioxidants, that get a lot of hype and attention. They may have a small positive effect on metabolism in later life, which would make them worth taking when cheap and safe. They are not in any way reversing aging - they are forcing a damaged machine to work harder without addressing any of the causes of failure. One can paint the same picture when discussing ways to enhance stem cell function without addressing the underlying damage, such as telomerase therapies and the use of signaling molecules. It may meet the cost-benefit equation, but it also may not, since these are much more expensive propositions.

Why is breaking extracellular crosslinks so important?

This is important because cross-links cause stiffening of tissues. The stiffening of blood vessels is the cause of hypertension, and hypertension is (like inflammation) a major way in which low-level biochemical damage is translated into many different forms of structural damage: pressure damage to delicate tissues; rupture of capillaries in the brain; remodeling and weakening of the heart; increased risk of atherosclerotic lesions causing stroke or heart attack. High blood pressure is very damaging. It is so harmful that ways to reduce blood pressure that work by overriding signaling systems - which do absolutely nothing to eliminate the root cause, the biochemical damage of aging - can still produce large reductions in mortality risk.

All of that can be greatly reduced by cross-link breaking, and there is only one major class of cross-links in humans that needs targeting to obtain that benefit: those involving glucosepane. Thus, like senolytics, once there is some motion towards achieving this end, we should see a very rapid expansion of the industry and delivery of benefits to patients. Glucosepane is hard to work with, so very few groups have done anything meaningful - the first big advance that the SENS Research Foundation achieved in this field was to fund the creation of the tools needed to move forward at all in this part of the field. Even now, there is really only one group working earnestly on it that I know of, David Spiegel's team at Yale, with a couple of others doing some investigative work around the edges of the challenge. The Spiegel approach is to mine the bacterial world for enzymes that degrade glucosepane and then refine the successes into therapeutic drugs. His team is a fair way along, and work is progressing in a funded startup company at this point.

Researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population and in HIV-infected people who are responding well to drugs. The team measured many markers on the surface of immune cells in the blood of people either with or without HIV (uninfected controls) that were sub-divided into two groups: younger (less than 35 years) and older (over 50 years) and compared that data with levels of inflammatory proteins in their plasma.

Researchers found a marker on these gamma delta T cells, called TIGIT, that tracked significantly with plasma inflammatory markers in both the HIV+ and uninfected subject groups, and therefore could be targeted to potentially stop this "inflammaging" found in both HIV+ people and the general geriatric population. "Our study indicates that there's a previously uninvestigated cell subset new player in the immune landscape that could be driving widespread illnesses and with targeted gamma delta therapeutics maybe there may be a chance of reducing onset, symptoms, and/or severity of inflammation-related diseases."