Cells called macrophages are one of the first responders in the immune system, with the job of "eating" invading pathogens. However, in patients with sepsis, the number of macrophages and other immune cells are lower than normal and they don't function as they should. In this study, researchers collected monocytes from the bone marrow of healthy mice and cultured them in conditions that transformed them into macrophages. The lab also developed vitamin-based nanoparticles that were especially good at delivering messenger RNA, molecules that translate genetic information into functional proteins.

The scientists, who specialize in messenger RNA for therapeutic purposes, constructed a messenger RNA encoding an antimicrobial peptide and a signal protein. The signal protein enabled the specific accumulation of the antimicrobial peptide in internal macrophage structures called lysosomes, the key location for bacteria-killing activities. From here, researchers delivered the nanoparticles loaded with that messenger RNA into the macrophages they had produced with donor monocytes, and let the cells take it from there to "manufacture" a new therapy.

After seeing promising results in cell tests, the researchers administered the cell therapy to mice. The mouse models of sepsis in this study were infected with multidrug-resistant Staphylococcus aureus and E. coli and their immune systems were suppressed. Each treatment consisted of about 4 million engineered macrophages. Controls for comparison included ordinary macrophages and a placebo. Compared to controls, the treatment resulted in a significant reduction in bacteria in the blood after 24 hours - and for those with lingering bacteria in the blood, a second treatment cleared them away.

Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals. Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis, and thus, alternative therapeutic approaches are urgently needed. Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression.

The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli, leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases.

Alzheimer's disease (AD) is a complex and multifactorial disease involving genetic and environmental risk factors that together lead to the progressive accumulation of two hallmark pathologies: β-amyloid plaques and neurofibrillary tangles (NFTs). Although many clinical trials have aimed to reduce β-amyloid and, more recently, to target the accumulation of tau that drives NFT formation, debate remains regarding which of these pathologies represents the most tractable target, and the precise timing for these potential treatments.

Recent longitudinal analyses demonstrated evidence of synergism between Aβ and phosphorylated tau (p-tau) suggesting these pathologies may interact to trigger the progression from amnestic mild cognitive impairment (MCI) subjects to AD dementia. PET imaging studies suggest that Aβ deposits start decades before dementia onset, and may or may not precede tau pathology, with the latter correlating better with symptom onset and the degree of dementia.

According to the modified amyloid cascade model, primary age-related tauopathy (PART) develops universally as a function of aging and, by itself, produces no or only mild cognitive symptoms. Aβ deposition occurs independently in the neocortex and induces or facilitates the spread of pathological tau, perhaps by promoting the production of pathological tau strains. Pathological tau is directly associated with neurodegeneration, which in turn drives cognitive decline. In this model of AD, Aβ does not directly cause cognitive symptoms but is still central to disease pathogenesis as a dominant driver of downstream pathological processes including tau pathology.

This synergistic model suggests that combinatorial/multi-target therapies directed at the accumulation of both amyloid and tau pathologies may be more effective in the treatment of AD than previously tested unimodal approaches. Recently, we demonstrated that the combination of AV-1959R and AV-1980R vaccines targeting Aβ and tau, respectively, induced robust antibody responses against various forms of both Aβ and tau pathological molecules in wildtype mice.

Here, we tested the therapeutic efficacy of co-formulated vaccines targeting Aβ and tau administered simultaneously in combination with AdvaxCpG adjuvant in the Tau22/5xFAD (T5x) mouse model of AD that develops highly aggressive Aβ and tau pathology. T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of T5x mice.

The researchers' approach starts with autophagy, a cellular "cleanup process" that removes and recycles damaged proteins and organelles. The autophagy process slows with age, which can lead to the weakening of cardiac muscles. The research team looked at a key genetic pathway conserved in virtually all organisms on Earth related to autophagy that balances organism growth with nutrient intake. This pathway, called mechanistic target of rapamycin (or mTOR), has long been linked to tissue aging. One of two complexes that underlie the mTOR pathway, referred to as mTORC2, decreases with age as autophagy declines. But the researchers found that transgenically boosting mTORC2 strengthens heart muscles of older fruit flies. "Boosting the complex almost fully restored heart function."

The discovery that enhancing mTORC2 slows the decline of the critical autophagy process could have big implications for how doctors treat patients with heart disease, one of the leading causes of the death. While flies and humans might seem to be worlds apart evolutionarily, the two species' hearts age in a similar fashion. By middle age, cardiac muscles in both species tend to contract with less strength and regularity.

Age-related impairment of macroautophagy/autophagy and loss of cardiac tissue homeostasis contribute significantly to cardiovascular diseases later in life. MTOR (mechanistic target of rapamycin kinase) signaling is the most well-known regulator of autophagy, cellular homeostasis, and longevity. The MTOR signaling consists of two structurally and functionally distinct multiprotein complexes, MTORC1 and MTORC2. While MTORC1 is well characterized but the role of MTORC2 in aging and autophagy remains poorly understood.

Here we identified TGFB-INHB/activin signaling as a novel upstream regulator of MTORC2 to control autophagy and cardiac health during aging. Using Drosophila heart as a model system, we show that cardiac-specific knockdown of TGFB-INHB/activin-like protein daw induces autophagy and alleviates age-related heart dysfunction, including cardiac arrhythmias and bradycardia. Interestingly, the downregulation of daw activates TORC2 signaling to regulate cardiac autophagy. Activation of TORC2 alone through overexpressing its subunit protein rictor promotes autophagic flux and preserves cardiac function with aging. In contrast, activation of TORC1 does not block autophagy induction in daw knockdown flies. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulation of these pathways in the heart has systemic effects on longevity control.

A new screening platform has enabled scientists to discover a set of drug-like compounds that may powerfully protect brain cells from dangerous stresses found in Alzheimer's and other neurodegenerative diseases. The screening platform allows researchers for the first time to rapidly test libraries of thousands of molecules to find those that provide broad protection to mitochondria in neurons. Mitochondria are tiny oxygen reactors that supply cells with most of their energy. They are especially important for the health and survival of neurons. Mitochondrial damage is increasingly recognized as a major factor, and in some cases a cause, for diseases of neuronal degeneration such as Alzheimer's, Parkinson's, and ALS.

The scientists, in an initial demonstration of their platform, used it to rapidly screen a library of 2,400 compounds, from which they found more than a dozen that boost the health of neuronal mitochondria and provide broad protection from stresses found in neurodegenerative disorders. The researchers are now testing the most potent of these mitochondria-protectors in animal models of Alzheimer's, amyotrophic lateral sclerosis, and other diseases, with the ultimate goal of developing one or more into new drugs. "It hasn't yet been emphasized in the search for effective therapeutics, but mitochondrial failure is a feature of many neurodegenerative disorders and something that must be corrected if neurons are to survive. So I'm a big believer that finding mitochondria-protecting molecules is the way to go against these diseases."

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from amyloid-β toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria.

The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

In 1851, the German physician Carl Reinhold August Wunderlich obtained millions of axillary temperatures from 25,000 patients in Leipzig, thereby establishing the standard for normal human body temperature of 37°C. A compilation of 27 modern studies, however, reported mean temperature to be uniformly lower than Wunderlich's estimate. Recently, an analysis of more than 35,000 British patients with almost 250,000 temperature measurements, found mean oral temperature to be 36.6°C.

In this study, we analyzed 677,423 human body temperature measurements from three different cohort populations spanning 157 years of measurement and 197 birth years. We found that men born in the early 19th century had temperatures 0.59°C higher than men today, with a monotonic decrease of -0.03°C per birth decade. Temperature has also decreased in women by -0.32°C since the 1890s with a similar rate of decline (-0.029°C per birth decade). Although one might posit that the differences among cohorts reflect systematic measurement bias due to the varied thermometers and methods used to obtain temperatures, we believe this explanation to be unlikely.

The question of whether mean body temperature is changing over time is not merely a matter of idle curiosity. Human body temperature is a crude surrogate for basal metabolic rate which, in turn, has been linked to both longevity (higher metabolic rate, shorter life span) and body size (lower metabolism, greater body mass). We speculated that the differences observed in temperature between the 19th century and today are real and that the change over time provides important physiologic clues to alterations in human health and longevity since the Industrial Revolution.

Resting metabolic rate is the largest component of a typical modern human's energy expenditure, comprising around 65% of daily energy expenditure for a sedentary individual. Heat is a byproduct of metabolic processes, the reason nearly all warm-blooded animals have temperatures within a narrow range despite drastic differences in environmental conditions. Over several decades, studies examining whether metabolism is related to body surface area or body weight, ultimately, converged on weight-dependent models. Since US residents have increased in mass since the mid-19th century, we should have correspondingly expected increased body temperature. Thus, we interpret our finding of a decrease in body temperature as indicative of a decrease in metabolic rate independent of changes in anthropometrics.

Although there are many factors that influence resting metabolic rate, change in the population-level of inflammation seems the most plausible explanation for the observed decrease in temperature over time. Economic development, improved standards of living and sanitation, decreased chronic infections from war injuries, improved dental hygiene, the waning of tuberculosis and malaria infections, and the dawn of the antibiotic age together are likely to have decreased chronic inflammation since the 19th century. For example, in the mid-19th century, 2-3% of the population would have been living with active tuberculosis. Although we would have liked to have compared our modern results to those from a location with a continued high risk of chronic infection, we could identify no such database that included temperature measurements. However, a small study of healthy volunteers from Pakistan - a country with a continued high incidence of tuberculosis and other chronic infections - confirms temperatures more closely approximating the values reported by Wunderlich.

In summary, our investigation indicates that humans in high-income countries have changed physiologically over the last 200 birth years with a mean body temperature 1.6% lower than in the pre-industrial era. The role that this physiologic 'evolution' plays in human anthropometrics and longevity is unknown.

It's not your imagination - the world is graying. In fact, by 2050, the global population age 65 and older is projected to nearly triple, to 1.5 billion. With this aging population, it will be more important than ever to reduce the burden of age-related disease. In the future, science will allow us to intervene in the aging process to make this a reality. It's imperative to keep our older population healthy and independent as long as possible. As this population grows, we'll need to provide help to increasing numbers of older people who are no longer independent. It will be a huge challenge for us as a society in the next 20 or 30 years.

Aging is a biological and physiological process like any other. We can learn how it works - how cells and molecules create what we see as "aging" in a person. Aging can be beautiful, but it is also the number-one risk factor or driver of most of the medical problems that we treat in adults: cancer, diabetes, dementia, Alzheimer's disease, cardiovascular disease, strokes, and heart attacks. The crazy thing is we can manipulate the aging process. We can adjust it. We can treat it. None of this is science fiction anymore. It's all science fact, right up to the part where people are conducting clinical trials of drugs that treat complex health problems through targeting molecular aging mechanisms. In geroscience, we seek to understand the relationship between aging, disease, and quality of life. The promise of this field is that by intervening in the process of aging, we could slow, prevent, delay, or reduce the risk of all sorts of diseases - all at the same time.

When visiting your primary physician in 2050, you'll have your aging mechanism risk factors checked, and you'll probably have preventive treatments. For example, we'll treat your senescent (old, inactive) cells or your autophagy (the process by which your body removes old, damaged proteins). If something is amiss in your risk factors, then we'll make adjustments. It'll just become part of regular preventive medicine.

Ex vivo manipulations of aged satellite cells have proven to be effective strategies to reverse some of the intrinsic alterations limiting their regenerative potential. These manipulations include genetic interventions to silence p16INK4a expression, thereby restoring quiescence and regenerative capacity to the aged satellite cell. Similarly, ex vivo pharmacological inhibition of p38 MAPK signaling decreases the expression of cell-cycle inhibitors, such as p16INK4a, and restores asymmetric division in satellite cells, contributing to enhanced regenerative potential of aged satellite cells in muscle transplantation experiments.

In vivo, local and systemic interventions have also shown promise in reversing age-related satellite cell defects. For example, systemic pharmacological treatments to restore basal autophagy flux preserved quiescence and muscle stem cell regenerative capacity in old muscles. Similarly, systemic delivery of oxytocin restores age-related regenerative capacity in old muscles, promoting satellite cell activation and proliferation, while systemic delivery of WISP1 during a regenerative event improves myogenic commitment and regenerative success. Moreover, systemic delivery of exogenous α-Klotho improves muscle stem cell bioenergetics and improves regenerative capacity in aged animals.

Rejuvenating interventions able to target the whole organism have also a positive impact on satellite cell function during aging. Successful interventions include caloric restriction, rapamycin treatment, supplementation with the NAD+ precursor nicotinamide riboside, senescent cell ablation, and in vivo reprogramming. These studies anticipate the existence of common hallmarks of aging associated with satellite cell loss of function in old animals, which can be considered common targets for intervention. Consistently, targeting chronic inflammation (a shared feature of several age-related pathologies) through systemic treatment with an inhibitor of NFκB activation improves myogenic function in aged satellite cells.

Aging increases aortic stiffness, contributing to cardiovascular risk even in healthy individuals. Aortic stiffness is reduced through supervised training programs, but these are not easily generalizable. The purpose of this study was to determine whether real-world exercise training for a first-time marathon can reverse age-related aortic stiffening. Untrained healthy individuals underwent 6 months of training for the London Marathon.

Assessment pre-training and 2 weeks post-marathon included central (aortic) blood pressure and aortic stiffness using cardiovascular magnetic resonance distensibility. Biological "aortic age" was calculated from the baseline chronological age-stiffness relationship. Change in stiffness was assessed at the ascending aorta (Ao-A) and descending aorta at the pulmonary artery bifurcation (Ao-P) and diaphragm (Ao-D).

A total of 138 first-time marathon completers (age 21 to 69 years, 49% male) were assessed, with an estimated training schedule of 6 to 13 miles/week. At baseline, a decade of chronological aging correlated with a decrease in Ao-A, Ao-P, and Ao-D distensibility by 2.3, 1.9, and 3.1 x 10^-3 mm/Hg, respectively. Training decreased systolic and diastolic central (aortic) blood pressure by 4 mmHg and 3 mmHg. Descending aortic distensibility increased (Ao-P: 9%; Ao-D: 16%), while remaining unchanged in the Ao-A. These translated to a reduction in "aortic age" by 3.9 years and 4.0 years (Ao-P and Ao-D, respectively). Benefit was greater in older, male participants with slower running times.

Paralysis following stroke is a leading cause of long-term motor disability. Brain machine interfaces (BMIs) can transform cortical activity into control signals for an external device, such as a robotic arm or computer cursor, and may provide a solution for restoring lost function. Bypassing the damaged pathway using brain-controlled functional electrical stimulation (FES) to regain volitional control of the paralysed limb is promising for restoring lost motor function. Brain-controlled FES works as an "artificial" neural pathway by creating a causal relationship between brain activity and an evoked limb movement. However, subjects may be required to learn a novel causal input-output relationship to control the paralysed limb.

Disruption of descending pathways, as can result from stroke, results in a lost connection between the brain and target muscles. Functional recovery in such a situation is characterised by substantial reorganisation in the structure and function of the damaged brain. Thus, our nervous system shows remarkable flexibility to adapt to novel neuromotor mappings. How the brain incorporates a novel "artificial" neural pathway into volitional limb control within the surviving cortical areas remains largely unclear.

In the present study, we generated a model of chronic hemiparalysis in the extremities caused by subcortical stroke in monkeys. We then employed an artificial cortico-muscular connection (ACMC) to connect the preserved cortical areas to muscles beyond the damaged site. Specific neural oscillations in the cortical area were detected contingent to the input and converted into electrical stimulation delivered to the muscles in real time. We demonstrated that, despite damage to subcortical areas, a flexible change in the neural oscillations controlling the ACMC was observed in a targeted manner throughout an extensive sensorimotor area. Thus, monkeys that experienced a subcortical stroke could rapidly learn to regain lost volitional control of a paralysed hand.

Recovery after stroke is a multicellular process encompassing neurons, resident immune cells, and brain-invading cells. Stroke alters the gut microbiome which in turn has considerable impact on stroke outcome. However, the mechanisms underlying gut-brain interaction and implications for long-term recovery are largely elusive. Here, we tested the hypothesis that short-chain fatty acids (SCFA), key bioactive microbial metabolites, are the missing link along the gut-brain axis and might be able to modulate recovery after experimental stroke.

SCFA supplementation in the drinking water of male mice significantly improved recovery of affected limb motor function. Using in vivo wide-field calcium imaging, we observed that SCFA induced altered contralesional cortex connectivity. This was associated with SCFA-dependent changes in dendritic spine and synapse densities. RNA-sequencing of the forebrain cortex indicated a potential involvement of microglial cells in contributing to the structural and functional re-modelling. Further analyses confirmed a substantial impact of SCFA on microglial activation, which depended on the recruitment of T cells to the infarcted brain.

Previous studies have shown a bi-directional communication along the gut-brain axis after stroke. Stroke alters the gut microbiota composition, and in turn, microbiota dysbiosis has a substantial impact on stroke outcome by modulating the immune response. However, until now the mediators derived from the gut microbiome affecting the gut-immune-brain axis and the molecular mechanisms involved in this process were unknown. Here, we demonstrate that SCFA - fermentation products of the gut microbiome - are potent and pro-regenerative modulators of post-stroke neuronal plasticity at various structural levels. We identified that this effect was mediated via circulating lymphocytes on microglial activation. These results identify SCFA as a missing link along the gut-brain axis and as a potential therapeutic to improve recovery after stroke.

Researchers looked at 34 years of data from 73,196 women and 28 years of data from 38,366 men participating in, respectively, the Nurses' Health Study and the Health Professionals Follow-up Study. Healthy diet was defined as a high score on the Alternate Healthy Eating Index; regular exercise as at least 30 minutes per day of moderate to vigorous activity; healthy weight as a body mass index of 18.5-24.9 kg/m2; and moderate alcohol intake as up to one serving per day for women and up to two for men.

They found that women who practiced four or five of the healthy habits at age 50 lived an average of 34.4 more years free of diabetes, cardiovascular diseases, and cancer, compared to 23.7 healthy years among women who practiced none of these healthy habits. Men practicing four or five healthy habits at age 50 lived 31.1 years free of chronic disease, compared to 23.5 years among men who practiced none. Men who were current heavy smokers, and men and women with obesity, had the lowest disease-free life expectancy.

"Previous studies have found that following a healthy lifestyle improves overall life expectancy and reduces risk of chronic diseases such as diabetes, cardiovascular disease, and cancer, but few studies have looked at the effects of lifestyle factors on life expectancy free from such diseases. This study provides strong evidence that following a healthy lifestyle can substantially extend the years a person lives disease-free."

There has been a longstanding belief among neuroscientists, backed by scientific evidence, that beta-amyloid, a protein that can clump together and form sticky plaques in the brain, is the first sign of Alzheimer's disease. The amyloid hypothesis, as it is often referred to, suggests an archetypal cascade in which β-amyloid in the brain initiates the acceleration of tau pathology, which in turn drives neurodegeneration and associated cognitive symptoms. However, now a new study is challenging the current hypothesis, with data suggesting that subtle thinking and memory differences may come before, or happen alongside, the development of amyloid plaques that can be detected in the brain.

"Our research was able to detect subtle thinking and memory differences in study participants and these participants had faster amyloid accumulation on brain scans over time, suggesting that amyloid may not necessarily come first in the Alzheimer's disease process. Much of the research exploring possible treatments for Alzheimer's disease has focused on targeting amyloid. But based on our findings, perhaps that focus needs to shift to other possible targets."

The study involved 747 people with an average age of 72. After adjusting for age, education, sex, genetic risk for Alzheimer's disease, and amyloid level at the start of the study, researchers found people with subtle thinking and memory differences had a more rapid accumulation of amyloid compared to people with normal thinking and memory skills. On a test that uses a dye to measure amyloid levels, where the average level was 1.16 for participants with subtle thinking and memory difficulties, amyloid levels in this group increased by .03 above and beyond the amyloid changes in those with normal thinking and memory skills over four years. People with subtle differences also had faster thinning of the entorhinal cortex, a brain region that is impacted very early in Alzheimer's disease.

On the other hand, researchers also found that, while people with mild cognitive impairment had more amyloid in their brains at the beginning of the study, they did not have faster accumulation of amyloid when compared to those with normal thinking and memory skills. However, they did have faster thinning of the entorhinal cortex as well as brain shrinkage of the hippocampus. "From prior research, we know that another biomarker of Alzheimer's disease, a protein called tau, shows a consistent relationship with thinking and memory symptoms. Therefore, more research is needed to determine if tau is already present in the brain when subtle thinking and memory differences begin to appear."

Nutrient malabsorption is common among the elderly, and often causes anemia and other illnesses. Nutrients are absorbed by the intestinal villi, which are composed of a layer of intestinal epithelial cells (IECs) and the lamina propria, and the absorption activity is affected by the size and density of villi. The epithelial layer is renewed every 4-5 days by intestinal stem cells (ISCs), which generate transient amplifying (TA) progenitor cells that later differentiate into absorptive or secretory cells. It has been reported that the number and regenerative activities of ISCs are decreased in 17 to 24-month-old mice, yet whether aging affects villus function and how villus aging is controlled remain less well understood.

mTOR, a sensor of nutrients and growth factors, is a central regulator of aging and a target for lifespan and healthspan extension. mTOR forms mTORC1 and mTORC2 complexes, and mTORC1 activation promotes cell proliferation by increasing global protein synthesis and other anabolic processes. mTORC1 signaling has been shown to be required for IEC proliferation during homeostasis and regeneration, including regeneration mediated by quiescent ISCs. In addition, several studies have shown that diet restriction promotes ISC expansion via mTORC1 signaling, although conflicting results have been reported regarding the exact roles played by mTORC.

The current genetic study reveals that mTORC1, which is hyperactivated in IECs, especially ISCs and TA cells of aged mice, drives villus aging by inhibiting ISC and progenitor cell proliferation through amplifying the MKK6-p38-p53 stress response pathway. This leads to ISC exhaustion and decreases in villus size and density. The natural function of the mTOR-MKK6-p38 MAPKs-p53 pathway may be to balance mTORC1-induced overgrowth and protect cells from runaway proliferation and oncogenic transformation, which is consistent with the concept that aging acts as an anti-hyperplasia mechanism.

Targeting p38 MAPK or p53 prevents or rescues ISC and villus aging and nutrient absorption defects. Inhibition of mTORC1 with rapamycin for only 1.5 months partially restored the structure and function of intestinal villi in old mice. These findings reveal that mTORC1 drives aging by augmenting a prominent stress response pathway in gut stem cells and identify p38 MAPK as an anti-aging target downstream of mTORC1.

The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported. The steady 26-year decline in overall cancer mortality is driven by long-term drops in death rates for the four major cancers - lung, colorectal, breast, and prostate, although recent trends are mixed. The pace of mortality reductions for lung cancer - the leading cause of cancer death - accelerated in recent years.

Overall cancer death rates dropped by an average of 1.5% per year during the most recent decade of data (2008-2017), continuing a trend that began in the early 1990s and resulting in the 29% drop in cancer mortality in that time. The drop translates to approximately 2.9 million fewer cancer deaths than would have occurred had mortality rates remained at their peak. Continuing declines in cancer mortality contrast with a stable trend for all other causes of death combined, reflecting a slowing decline for heart disease, stabilizing rates for cerebrovascular disease, and an increasing trend for accidents and Alzheimer's disease.

Lung cancer death rates have dropped by 51% (since 1990) in men and by 26% (since 2002) in women, with the most rapid progress in recent years. For example, reductions in mortality accelerated from 3% per year during 2008-2013 to 5% per year during 2013-2017 in men and from 2% to almost 4% in women. However, lung cancer still accounts for almost one-quarter of all cancer deaths, more than breast, prostate, and colorectal cancers combined.

The most rapid declines in mortality occurred for melanoma of the skin, on the heels of breakthrough treatments approved in 2011 that pushed one-year survival for patients diagnosed with metastatic disease from 42% during 2008-2010 to 55% during 2013-2015. This progress is likewise reflected in the overall melanoma death rate, which dropped by 7% per year during 2013-2017 in people ages 20 to 64, compared to declines during 2006-2010 (prior to FDA approval of ipilimumab and vemurafenib) of 2%-3% per year in those ages 20 to 49 and 1% per year in those ages 50 to 64. Even more striking are the mortality declines of 5% to 6% in individuals 65 and older, among whom rates were previously increasing.

We obtained RNA sequencing data of subjects ranging from newborns to centenarians from a previous study, and summarized the data into a relative abundance matrix of genera in all the samples. Without using the age information of samples, we applied an unsupervised algorithm to recapitulate the underlying aging progression of microbial community from hosts in different age groups and identify genera associated to this progression. Literature review of these identified genera indicated that for individuals with advanced ages, some beneficial genera are lost while some genera related with inflammation and cancer increase.

A few genera were previously implicated in the literature, such as Oxalobacter, Butyrivibrio, Lactobacillus which have been experimentally demonstrated to be associated with aging, as well as Prevotellaceae which has been highlighted with lower presence in the gut microbiota of centenarians. The abundances of some other genera increased with respect to aging, but decreased in the extremely elderly subjects. Among these genera, Lactobacillus species are commonly used as probiotics. Oscillospira species have been frequently reported as enriched in lean subjects compared to the obese subjects, and are central to the human gut microbiota for degrading fibers. Oxalobacter is responsible for degrading oxalate in the gut. It has been experimentally demonstrated appearing in the gut of almost all young individuals, but these bacterium may later be lost during aging.

Prevotellaceae is commonly found in the gastric system of people who maintain a diet low in animal fats and high in carbohydrates and is lost in centenarians. Researchers also found that there was an increased abundance of Prevotellaceae in the guts of healthy people compared with people with Parkinson's disease. Parascardovia is a genus of Bifidobacteriaceae, which has been shown to provide health-promoting benefits to the host. Butyrivibrio species have been experimentally proved as butyrate producing bacteria, and butyrate is a preferred energy source for colonic epithelial cells and is thought to play an important role in maintaining colonic health in humans. Overall, the decrease of these beneficial genera in the elderly age groups, especially centenarians, maybe manifestation of or causal associations to decline of health in those age groups.