Iron is an electron facilitator and is involved in many brain functions, including oxygen transport, myelin production, electron transfer, and neurotransmitter synthesis. Both imaging and postmortem analyses have shown that the concentration of iron in the brain is not uniform. Previous studies have demonstrated that iron accumulates in the normal aging brain, which might damage cognitive function. However, the exact mechanism of iron deposition in the aging brain remains unclear.

Recent work has led to the discovery of the "glymphatic system," which is a coined phrase that combines "gl" for glia cell with "lymphatic system". Within the glymphatic system, cerebrospinal fluid enters the brain via peri-arterial spaces, passes into the interstitium via astrocytic aquaporin-4, and then drives the peri-venous drainage of interstitial fluid and its solute. Evidence suggests that the glymphatic system is an important fluid clearance system in the brain. Numerous neurological disorders have been found to be closely related to the dysfunction of the glymphatic system, including Alzheimer's disease and Parkinson's disease.

Evidence also revealed that iron deposition was one of the most important underlying mechanisms in Alzheimer's disease and Parkinson's disease. Some scholars also believe that the glymphatic system may be the major contributory factor to the deposition and clearance of iron in brain tissue, but evidence is still lacking. In this study, we recruited 213 healthy participants. We evaluated the function of the glymphatic system using the index for diffusivity along the perivascular space (ALPS-index), assessed iron deposition on quantitative susceptibility mapping (QSM), and analyzed their relationship. The main finding of the current study is that the regional brain iron deposition was related to the function of the glymphatic system.

Previously, the glymphatic system has been speculated to be responsible for the clearance and homeostasis of waste in the brain. Our results support that in a healthy aging brain, the glymphatic system might also be involved in the clearance of iron, suggesting that iron metabolism shared the same pathway as other waste metabolisms. Moreover, a study has demonstrated that injury of the microvasculature and capillary-level microhemorrhages coincided with amyloid beta (Aβ) deposits in senile plaques. Iron deposition plays an important role in cerebral small vessel diseases. Therefore, we inferred that dysfunction of the glymphatic system might lead to the damage of microvasculature via deposition of Aβ, then leading to iron deposition.

Aging and diabetes are identified as risk factors associated with increased intervertebral disk (IVD) degeneration degeneration and back pain. These associations may be attributed to chronic proinflammatory conditions, yet these associations are confounded by environmental and genetic factors, making causal relationships difficult to identify. A leading hypothesis for a relationship between diabetes and IVD degeneration is the formation and accumulation of advanced glycation end products (AGEs) in diabetic IVD tissue. AGEs are highly oxidant compounds that accumulate in aging and are implicated in diabetic complications that are known to cause structural and biological alterations to collagen and the extracellular matrix (ECM).

There is mounting evidence for a causal relationship between IVD degeneration and AGEs. AGEs can accumulate in spinal tissues from aging, high-AGE (H-AGE) diets (eg, highly processed western diets) and diabetes, and are associated with structural changes in the IVD including decreased glycosaminoglycan content, increased vertebral bone changes, and increased collagen degradation. In addition, the receptor for AGEs (RAGE) has been observed to initiate an NF-kB mediated inflammatory response in both human and mice IVD tissue exposed to AGEs.

The specific structural changes to the IVD ECM due to AGE exposure in the presence of RAGE are not well-understood and we believe this is partly due to limitations in the methods used to identify early degenerative changes to the ECM that mark the initiation of a degenerative cascade. Recently, we demonstrated that dietary accumulation of AGEs in the IVD increased levels of molecular level collagen degradation, highlighting the direct contributions that AGEs can make to IVD degeneration.

This two-part study used in vivo and ex vivo IVD model systems with wild type and RAGE-knockout (RAGE-KO) mice in order to investigate changes in AF collagen quality and degradation in response to AGE challenges. First, we used SHG imaging on thin sections with an in vivo dietary mouse model and determined that high-AGE (H-AGE) diets increased annulus fibrosus (AF) fibril disruption and collagen degradation resulting in decreased total collagen content, suggesting an early degenerative cascade. Next, we used in situ imaging with an ex vivo IVD organ culture model of AGE challenge on wild type and RAGE-knockout (RAGE-KO) mice and determined that early degenerative changes to collagen quality and degradation were RAGE dependent. We conclude that AGE accumulation leads to RAGE-dependent collagen disruption in the AF and can initiate molecular and tissue level collagen disruption.

The prevalence of chronic kidney disease (CKD) has reached epidemic proportions, with approximately 10% of the total population show declined kidney function. Actually, during the disease progression, the majority of lesions develop into the end-stage renal disease (ESRD), a devastating condition that requires renal replacement treatment, including kidney transplant and dialysis. Remarkably, CKD not only shares numerous phenotypic similarities with kidney ageing, such as glomerular sclerosis, interstitial fibrosis, tubular atrophy, loss of repair capability, and vascular rarefaction, but also exhibits systemic geriatric phenotypes, for instance vascular calcification, persistent uraemic inflammation, cognitive dysfunction, muscle wasting, osteoporosis, and frailty.

The most common markers applied to identify cellular senescence include the overexpression of cyclin-dependent kinase (CDK) inhibitors such as p16ink4a and p21. Interestingly, the expression levels of p16ink4a and the activity of SA-β-gal are elevated in different stages of CKD and some kinds of original kidney diseases. These unexpected alternations indicate that cellular senescence may play important roles in the progression of CKD. The precise roles of cellular senescence in CKD are not fully understood currently. Nonetheless, it is proposed that targeting senescent cells in the kidney might serve as a novel therapeutic strategy for CKD treatment.

Numerous studies have demonstrated that the selectively elimination of senescent cells contributes to the improvement of healthy lifespan and benefits the outcomes of a wide range of age-related diseases. Some of them have shown significant potentials in reversing renal ageing. For example, the combination of dasatinib and quercetin, referred as "D + Q", is an effective senolytic and reduces the overall senescent cell burden in chronologically aged mice. Actually, D + Q has been tested in ageing diabetic kidney disease patients, and the administration of D + Q showed reduced adipose tissue p16ink4a and p21 expression, SA-β-gal activity, and circulating SASP-acquisition factors. Other senolytic molecules, such as Flavonoids (e.g., apigenin and kaempferol) have been proved to strongly inhibit the SASP acquisition in the kidney of aged rats. These findings have opened an exciting new therapeutic avenue for the treatment of CKD and its complications via selectively targeting senescent cells.

Sixty years ago, Nathan Shock created the Baltimore Longitudinal Study of Aging, and his idea was that we needed to dissociate aging from disease, because only at that point would we know what disease is and how to treat patients. There was an interest in trying to understand aging so that we could ignore it, because there was nothing that we could do about it. And then, as researchers started to look at aging and began searching for the point of dissociation between aging and disease, they found that it was much more difficult than expected. As our technologies became more developed and sophisticated, the boundaries between aging and diseases continued to blur.

The risk factor paradigm started with cardiovascular and cancer epidemiology; the basic idea is that if you wait a certain amount of time, risk factors will trigger a disease. People initially thought that there was some specificity between risk factors and diseases, but over time we have discovered that this specificity was not really there. Exercise and physical activity can reduce the risk of developing cardiovascular diseases, cancers, pulmonary diseases, sarcopenia, and so on. Smoking increases the risk of developing these diseases, too. You can say the same thing for many different risk factors that are being considered. Cancer and cardiovascular disease, the two major causes of mortality, share many of the same risk factors. Think about obesity: it's associated with most chronic diseases that you can think of. And so there has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease. And I think that it makes a lot of sense.

This explains why aging is a much stronger risk factor for dementia than carrying an APOE4 allele. This shift in thinking is important because it places aging at the forefront of medicine. Now, if this is true, understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan. This shift creates incredible opportunities, and even private companies have started to become interested in studying aging.

Recent studies demonstrated that altered energy homeostasis associated with reduced cerebral glucose uptake and utilization, altered mitochondrial function and microglia and astrocyte activation might underlie neuronal dysfunction in Alzheimer's disease (AD). Intriguingly, accumulating evidence suggests that non-pharmacological approaches, such as diet and exercise, reduce major AD hallmarks by engaging an adaptive stress response that leads to improved metabolic state, reduced oxidative stress and inflammation, and improved proteostasis. While mechanisms of the stress response are complex, AMP-activated protein kinase (AMPK)-mediated signaling has been directly linked to the regulation of cell metabolism, mitochondrial dynamics and function, inflammation, oxidative stress, protein turnover, Tau phosphorylation, and amyloidogenesis. However, the development of direct pharmacological AMPK activators to elicit beneficial effects has presented multiple challenges.

We recently demonstrated that mild inhibition of mitochondrial complex I (MCI) with the small molecule tricyclic pyrone compound CP2 blocked cognitive decline in transgenic mouse models of AD when treatment was started in utero through life or at a pre-symptomatic stage of the disease. Moreover, in neurons, CP2 restored mitochondrial dynamics and function and cellular energetics. However, it was unclear whether MCI inhibition would elicit similar benefits if administered at the advanced stage of the disease, after the development of prominent Aβ accumulation, brain hypometabolism, cognitive dysfunction, and progressive neurodegeneration. As a proof of concept, we demonstrate that partial inhibition of MCI triggers stress-induced AMPK-dependent signaling cascade leading to neuroprotection and a reversal of behavior changes in symptomatic APP/PS1 female mice, a translational model of AD. Beneficial effect of treatment could be monitored using translational biomarkers currently utilized in clinical trials.

The mitochondrial permeability transition pore (mPTP) is a mitochondrial inner membrane multicomponent mega-channel that is activated by calcium, oxidative stress, and membrane depolarization. The channel exhibits several conductance states with variable duration. When activated, protons flow into the matrix, while calcium, superoxide, hydrogen peroxide, and other ions flow out of the matrix, thus inhibiting oxidative phosphorylation.

It is now recognized that mitochondrial dysfunction is a major contributor to aging and aging-driven degenerative disease, such as diabetes, heart diseases, cancer, Alzheimer's disease, and Parkinson's disease. Mitochondrial dysfunction in aging is often manifested as the excess production of mitochondrial reactive oxygen species (mROS), calcium overloading, and membrane depolarization. Since these dysfunctions are known to activate mPTP, it can be expected that mPTP activity will be enhanced in dysfunctional mitochondria in aging. Indeed, direct evidence for enhanced mPTP activation in aging and neurodegenerative disease is extensive.

mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+, and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.

The increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.

When researchers surgically conjoin the circulatory systems of a young and an old animal, something remarkable happens: the older animal recovers some features of youth, while the young animal becomes functionally older. This phenomenon is called heterochronic parabiosis. A possible player in the pro-aging/rejuvenating effects of parabiosis that has been largely ignored until recently is the potential role of metabolic toxins and wastes. In addition to the cellular and molecular damage of aging that accumulates in our bodies over time, the body's normal metabolic processes also produce an enormous amount of more transient metabolic waste every day. In youth, much of what could go to waste is instead reprocessed and reused, and the rest is detoxified and excreted.

As we age, however, the organs responsible for detoxifying and eliminating these wastes - the kidneys, the liver, and to a lesser extent the lungs - age along with the rest of us, and their ability to remove these wastes progressively degrades. As a result, waste levels in blood circulation rise with age. These metabolic toxins are definitely bad for us - just ask a patient waiting for a liver transplant or on haemodialysis. Consistent with this, a biomarker called cystatin C, the most reliable marker of loss of kidney function, is a powerful predictor of broader age-related decline.

At the urging of SENS Research Foundation CSO Aubrey de Grey, and with SRF funding, pioneering parabiotic researchers Michael and Irina Conboy conducted a study to tease out the role of access to a young animal's organs in the parabiosis effect in 2015. Researchers built a machine capable of exchanging volumes of blood at will, replacing them with equal volumes of blood (or plasma, or other substitute fluid). They found that the benefits of directly trading old blood for young were dramatically less impressive than the effects of full-on parabiosis complete with the filtering and detoxification services provided by young liver and kidney function.

On the other hand, receipt of young blood did enhance the repair of old animals' muscles after injury, although the effects were less impressive than what's seen in parabiosis - and in this case, there was no inhibitory effect on the muscles of young animals exposed to old blood. Similarly, the ability of an old animal's injured liver to regenerate was enhanced by young blood, and existing age-related fibrosis improved. These experiments show that these health effects are not mediated primarily by removal of metabolic wastes, though certainly they could still be mediated by dilution effects rather than true active-factor transfers.

By this point, a direct test of the dilution hypothesis would seem to be in order - and recently the Conboys ran one. With the blood-replacement machine up and running, they replaced half the blood of old mice - not with young blood, but with saline solution, plus an amount of the albumin protein family equivalent to that in blood, to avoid losing albumin's important non-signaling functions in transporting different substances around the body. Like young blood itself, this "neutral blood exchange" (NBE) substitute (as they called it) would lack all of the pro-aging factors that an old mouse's blood would contain (as well as the metabolic sludge its aging organs would have failed to remove) - but, importantly, would not contain any of the pro-youth molecules that some think are responsible for the effects of heterochronic parabiosis.

Remarkably, a single NBE treatment rejuvenated muscle repair capacity of old mice to equivalent levels of quite young control animals, including major improvements in the number of muscle stem cells engaged to regenerate the damaged muscle, the area of muscle where such cells were active, and in the level of fibrosis left behind. NBE also significantly improved liver health in old animals, partially reversing their fibrosis and reducing the pathological fat deposits in the organ.

Will life-extension treatments be prohibitively expensive? The diabetes drug metformin is a classic candidate for a possible anti-aging pill. And the cost of this possible wonder drug? Retail costs for 60 tablets of 500mg of metformin (a 1-2 month supply) range from 9 to 16, even without insurance. Other potential life-extension molecules are similarly cheap. Glucosamine costs as little as ten cents a pill, has been the subject of several recent studies showing it decreases all-cause mortality by as much as 39%, and may be as effective for longevity as exercise.

What about newer anti-aging medicines? Is there evidence that newly discovered and developed drugs would be similarly inexpensive? It's likely. Take vaccines. Vaccines are a good parallel to anti-aging medicines because they are developed to treat a deadly, widespread disease that impacts large swaths of the human population and they thus have a huge demand and a requirement to distribute to the most people possible. Developing a vaccine can cost as much as 2.8-3.7 billion and yet many vaccines, including those for the most widespread diseases, are offered free-of-cost or at very low prices. For example, the flu vaccine is often free and almost always fully-covered by insurance. Other vaccines can be had, even without insurance, for as low as 6.

If, despite the above, life-extension treatments are expensive, if they are gene therapies for example, will they remain so? In the last 17 years, the cost to have your whole genome sequenced has gone from roughly 1 billion in 2003, to as low as 299 today. And most technological innovation follows this same pattern. First an experimental, expensive innovation is developed. Wealthy early-adopters buy it (think investment bankers and car phones back in the 80s), and their purchases fund the research and development needed to improve the innovation, better distribute it, and make it less expensive. Soon, every person who wants one can afford it, and at a much higher level of quality than the original that was available only to the rich.

High initial prices of a new product are thus almost an extended form of R&D funding (and clinical testing with data provided by early adopters). The rich are essentially paying the money necessary to further develop the product and get it to the masses. What the rich pay for with money, the poor pay for with time. It's the reason the smartphone in your pocket only costs a couple hundred, and you don't need to lug a car around to use it. It's also the reason your Apple Watch isn't the size of a room, and yet can do way more health monitoring than the early electrocardiogram machines could (and at a significantly lower price).

Intuitively, anti-aging medicine should even help lower the total cost of medical care for people, as individuals will have to spend less on treating the very expensive chronic diseases of old-age like Alzheimer's or cancer. These health-cost savings from longevity medicine are often referred to as the "Longevity Dividend." Contrary to popular belief, the real money in almost any market is not in selling boutique treatments to a few billionaires, but selling commercialized interventions to the millions (and, globally, billions) in the middle and lower classes.

Researchers have established a mouse model to help them understand why some hosts' immune systems reject tumors easily, while others have a harder time doing so. The scientists started the research by transplanting tumors into genetically identical mice. Theoretically, their response to the cancer would be identical, but it turned out that 25% of the mice spontaneously rejected the tumor. The researchers started looking more closely at both the mice and the tumor cells to try to understand what was causing the mice to kill the cancer on their own.

What they discovered is that it all depended on the types of the immune cells known as CD8 T cells that were present in the mouse. Even identical twins have different T cells due to the random DNA recombination event generating these T cells, so the genetically identical mice had different arrays of the T cells as well. The mice's response to cancer depended on how their specific T cells matched up with the set of mutated proteins known as neoantigens that were present in the tumor they were fighting.

"Each of your T cells has a different receptor, and each T cell will be specific to a neoantigen. If you have T cells that are specific to all of them or majority of them, you're going to be able to get rid of your tumor and have a good anti-tumor immune response." The researchers showed that the mice that spontaneously rejected tumors had vastly different T cell receptors from those that succumbed to tumor development.

Hormesis is any kind of biphasic dose-response when low doses of some agents are beneficial while higher doses are detrimental. Radiation hormesis is the most thoroughly investigated among all hormesis-like phenomena, in particular in biogerontology. In this review, we aim to summarize research evidence supporting hormesis through exposure to low-dose ionizing radiation (LDIR). Radiation-induced longevity hormesis has been repeatedly reported in invertebrate models such as C. elegans, Drosophila, and flour beetles and in vertebrate models including guinea pigs, mice, and rabbits. On the contrary, suppressing natural background radiation was repeatedly found to cause detrimental effects in protozoa, bacteria, and flies.

We also discuss here the possibility of clinical use of LDIR, predominantly for age-related disorders, e.g., Alzheimer's disease, for which no remedies are available. There is accumulating evidence that LDIR, such as those commonly used in X-ray imaging including computer tomography, might act as a hormetin. Of course, caution should be exercised when introducing new medical practices, and LDIR therapy is no exception. However, due to the low average residual life expectancy in old patients, the short-term benefits of such interventions (e.g., potential therapeutic effect against dementia) may outweigh their hypothetical delayed risks (e.g., cancer). We argue here that assessment and clinical trials of LDIR treatments should be given priority bearing in mind the enormous economic, social, and ethical implications of potentially-treatable, age-related disorders.

In contrast to the short and very frequent fasting periods of intermittent fasting (IF), periodic fasting (PF) or a fasting mimicking diet (FMD) last in most cases between 2 and 7 days (2-3 days in mice and 4-7 days in humans) and are followed by a high-nourishment refeeding period of at least 1 week. Another major difference from IF is that PF can be periodic and does not have to be carried out at a specific interval, but can be applied for one or several cycles either as a preventive measure or to treat a specific disease or condition. FMDs were developed to promote the effects of fasting while standardizing dietary composition, providing nourishment and minimizing the burden and side effects associated with water-only fasting. These steps are necessary for PF and possibly IF to move toward approval from the US Food and Drug Administration and standard-of-care applications.

Sixteen-month-old female C57BL/6 mice placed on a periodic 4-day FMD twice per month, alternating with a normal diet, display an 11% increase in their median lifespan, in addition to significant weight and visceral-fat loss, without loss of muscle mass. Moreover, FMD cycles reduce tumor incidence by 45% and delay tumor development. Notably, the FMD cycles also promote changes leading to an immune-system profile in 20.5-month-old mice more similar to that of younger mice (4 months old), in agreement with the effect of PF on hematopoietic stem cell (HSC)-dependent regeneration of immune cells.

In summary, similarly to the well-established effects of calorie restriction, FMD cycles delay the onset and reduce the incidence of age-related diseases, but achieve this with minimal or no long-term reduction in calorie intake and with positive effects on immunity and a targeted reduction in visceral fat. Thus, PF/FMD but potentially also certain dietary restrictions, including IF, may achieve many beneficial effects by mechanisms that are independent of reduced calorie intake.

Efficient skeletal muscle bioenergetics hinge on mitochondria, and mitochondrial dysfunction is recognized as a major hallmark of aging. Indeed, protecting mitochondria is a determinant to preserve proteostasis in skeletal muscle. To date, a growing body of evidence on mitochondrial impairment in sarcopenia has been provided by both animal and human studies. Dysfunctional mitochondria are associated with both ATP depletion and ROS/RNS excess, with the consequent activation of harmful cellular pathways. A decrease in mitochondrial mass, activity of tricarboxylic acid cycle enzymes, as well as O2 consumption and ATP synthesis occurs in aged skeletal muscle tissue. Changes in function, dynamics, and biogenesis/mitophagy could explain in part alteration in oxidative capacity and content of skeletal muscle mitochondria. Furthermore, mitochondrial dysfunction induces the activation of apoptosis, potentially impairing skeletal muscle quality.

Several mitochondrial functions are impaired in old in comparison to young skeletal muscle, including the activity of metabolic enzymes and oxidative phosphorylation (OXPHOS) complexes (i.e., citrate synthase and cytochrome c oxidase), respiration, protein synthesis, and ATP production rate. The reduced mitochondrial content in aged skeletal muscle may be also related to lower PGC-1α gene and protein expression. However, the molecular mechanisms that underpin this reduction are worth further investigation. Apart from PGC-1α, different studies show divergent results in the levels of its downstream transcription factor Tfam in old skeletal muscle.

Changes related to mitochondrial content and function in old skeletal muscle may also be related to a reduced amount, increased mutations, deletions, and rearrangements of mitochondrial DNA (mtDNA). A greater prevalence of mtDNA deletion mutations is described in skeletal muscle fibers, which were more subjected to oxidative damage. An age-dependent increase in skeletal muscle fibers presenting with alterations of mitochondrial enzymes due to mtDNA deletion mutations is reported both in rhesus monkeys presenting with early-stage sarcopenia and in humans.

Morphological studies in aged skeletal muscle show giant mitochondria with disrupted cristae. Altered morphology in old skeletal muscle mitochondria may be the consequence of impaired mitochondrial dynamics, with a disbalance in favor of fission rather than fusion. Mutations in mtDNA may lead to dysregulation of mitochondrial dynamics in sarcopenia, as suggested by results from old mice expressing a defective mtDNA polymerase gamma, which showed higher mitochondrial fission in skeletal muscle. A shift toward mitochondrial fusion rather than fission was also reported in skeletal muscle of very old hip-fractured patients.

The reduced capacity of skeletal muscle cells to remove damaged organelles could be another cause of mitochondrial alteration in aging. Studies performed on rodent models describe controversial results on mitophagy modulators in aged skeletal muscle. A further investigation reported data indicative of increased mitophagy but lysosomal dysfunction in skeletal muscle from old mice, suggesting that lysosomal dysfunction may cause accumulation of disrupted mitochondria. Nevertheless, further investigation on the role of mitophagy in old skeletal muscle is needed in humans.

In the 1920s, German chemist Otto Warburg discovered that cancer cells don't metabolize sugar the same way that healthy cells usually do. Since then, scientists have tried to figure out why cancer cells use this alternative pathway, which is much less efficient. Researchers have now found a possible answer to this longstanding question. They showed that this metabolic pathway, known as fermentation, helps cells to regenerate large quantities of a molecule called NAD+, which they need to synthesize DNA and other important molecules. Their findings also account for why other types of rapidly proliferating cells, such as immune cells, switch over to fermentation.

Fermentation is one way that cells can convert the energy found in sugar to ATP, a chemical that cells use to store energy for all of their needs. However, mammalian cells usually break down sugar using a process called aerobic respiration, which yields much more ATP. Cells typically switch over to fermentation only when they don't have enough oxygen available to perform aerobic respiration. Warburg originally proposed that cancer cells' mitochondria, where aerobic respiration occurs, might be damaged, but this turned out not to be the case. Other explanations have focused on the possible benefits of producing ATP in a different way, but none of these theories have gained widespread support.

Researchers treated cancer cells with a drug that forces them to divert a molecule called pyruvate from the fermentation pathway into the aerobic respiration pathway. They saw that blocking fermentation slows down cancer cells' growth. Then, they tried to figure out how to restore the cells' ability to proliferate, while still blocking fermentation. One approach was to stimulate the cells to produce NAD+, a molecule that helps cells to dispose of the extra electrons that are stripped out when cells make molecules such as DNA and proteins. When the researchers treated the cells with a drug that stimulates NAD+ production, they found that the cells started rapidly proliferating again, even though they still couldn't perform fermentation.

This led the researchers to theorize that when cells are growing rapidly, they need NAD+ more than they need ATP. During aerobic respiration, cells produce a great deal of ATP and some NAD+. If cells accumulate more ATP than they can use, respiration slows and production of NAD+ also slows. Therefore, switching to a less efficient method of producing ATP, which allows the cells to generate more NAD+, actually helps them to grow faster. "Not all proliferating cells have to do this. It's really only cells that are growing very fast. If cells are growing so fast that their demand to make stuff outstrips how much ATP they're burning, that's when they flip over into this type of metabolism. So, it solves, in my mind, many of the paradoxes that have existed."

One approach to identify new traits responsible for aging is to compare how these traits change with age in control and long-lived animals of the same species. For example, centenarians have a distinctive epigenetic profile compared to an age-matched control population. Similarly, we previously showed that flies with increased longevity have dramatic differences in many metabolites associated with methionine metabolism even at 1 week of age when 100% of both control- and long-lived flies are still alive.

To identify novel metabolic pathways that correlate with lifespan and that can be responsible for aging, we compared the metabolome of 1-week- and 4-week-old wild-type and long-lived flies to identify changes in metabolites that correlate with lifespan and identified tyrosine as an age-dependent metabolite. We demonstrate that Drosophila has a single tyrosine aminotransferase (TAT). Whole-body or neuronal-specific downregulation of TAT as well as other downstream enzymes in the tyrosine degradation pathway significantly extend Drosophila lifespan, cause alterations of multiple metabolites associated with increased lifespan, and lead to an increase in tyrosine and tyrosine-derived neuromediators (dopamine, octopamine, and tyramine). We further demonstrate that mitochondrial dysfunction may serve as an age-dependent stimulus that redirects tyrosine from neuromediator production into mitochondrial metabolism.

In conclusion, our studies highlight the important role of the tyrosine degradation pathway and position TAT as a link between neuromediator production, dysfunctional mitochondria, and aging.