Fight Aging! Newsletter, August 23rd 2021

The FDA's controversial approval of aducanumab hinged on the premise that clearance of amyloid would be "reasonably likely" to bestow a cognitive benefit. Data presented at the Alzheimer's Association International Conference (AAIC) support the idea that two other antibodies could clear that low bar, as well. Researchers reported that the plaque-dissolving strength of donanemab, an antibody trained against forms of amyloid-β (Aβ) detectable only in plaques, tracked closely with plummeting plasma p-tau217. Weaving their data into a disease-progression model that had been generated from past trial data, they claimed that the amyloid- and tau-lowering effects of the drug correlated with a slowing of cognitive decline. Separately, data from lecanemab's Phase 2 trial and open-label extension studies provided yet more support for that antibody's disease-modifying effect, despite the travails that have beset its path through clinical development.

Both donanemab and lecanemab have received breakthrough therapy status from the FDA. Similarly to aducanumab, this means that their sponsors could apply for accelerated approval based primarily on changes in surrogate biomarkers that demonstrate amyloid reduction.

The donanemab trial enrolled 257 participants who had early symptomatic AD, amyloid in their brains, and - notably - an intermediate level of neurofibrillary tangles based on PET scan. After an initial period, when 131 volunteers randomized to the treatment group gradually received higher and higher doses of donanemab, the trial settled in on monthly infusions of 1,400 mg donanemab. This was given until a person's amyloid burden dropped below 25 centiloids - the level in healthy young controls - at which point the dose was lowered to 700 mg. If amyloid fell below 11 centiloids, or below 25 for two consecutive scans, the person was switched to placebo.

The 76-week trial met its primary cognitive endpoint, showing a 32 percent slowing of decline on the Integrated Alzheimer's Disease Rating Scale (iADRS). By 24 weeks, donanemab had completely cleared plaques in 40 percent of participants in the treatment group; by the trial's end, 68 percent had reached normal levels. Once a person's amyloid complete cleared, their levels stayed down for the remainder of the trial. Among the participants with "deep amyloid clearance," i.e., amyloid levels below 11 centiloids, and who were switched to placebo by 24 weeks, amyloid burden crept up only slowly by 76 weeks, barely cresting 11 centiloids, on average. At this rate, it would take 14 years for amyloid to accumulate back to baseline level for this group, or about 90 centiloids.

Adult skeletal muscles decline in size with age, resulting in a loss of muscle mass (sarcopenia) and consequent weakness. The impact of muscle loss is exacerbated by the corresponding decline in the quality of the preserved muscle (e.g., amount of force per unit volume). These deficits, together with increased susceptibility to injury, reduced recovery, and proprioceptive decline, predispose the risk of falls and related injuries, which are linked to morbidity and mortality. Sarcopenia has enormous social and economic benefits: a 10% reduction in prevalence alone would result in savings of well over a billion in expenditure. Despite significant advances in understanding the molecular alterations in aging, the pathophysiology of age-associated muscle weakness remains unclear.

Some describe sarcopenia as a primary muscular pathology, with only minimal changes in the peripheral nerves and motor units occurring much later than the onset of sarcopenia. Indeed, aging muscles share several similarities to muscle dystrophies. Synaptic nuclei in aged muscle have abnormal expression of nuclear proteins, such as reduced LMNA gene expression, suggesting that muscle dysfunction with aging may be similar to that seen in laminopathies. Other similarities between aging muscle and dystrophic muscle include a loss of dystrophin with age. However, there is no consensus on other components of the dystrophin glycoprotein complex (DGC), with reports of increased, decreased and unchanged expression of DGC components.

However, the diminished muscle quality suggests additional neural contributions of to muscle wasting. A number of age-associated pathological changes have been reported in peripheral nerves and neuromuscular junctions (NMJs), which have even been posited to initiate and drive the muscle pathology in sarcopenia. There are strong correlations between aging and deficits in axonal transport in peripheral neurons. These deficits impair the delivery of vital synaptic and energetic cargoes to the pre-synaptic terminal and occur concurrent with age-associated changes in the neuronal cytoskeleton. Neurofilaments, the primary structural components of motor neurons and a key regulator of axonal caliber and cytoskeletal transport, appear particularly susceptible to age, based on observed changes in their density, organization, and phosphorylation state in aged mice.

Just as the NMJ dictates muscle physiology, it also influences muscle pathology. Several lines of evidence suggest that age-related changes in the NMJ play a key role in musculoskeletal impairment with aging. Indeed there is increasing consensus that functional muscle denervation is a principal factor leading to sarcopenia, and some even describe sarcopenia primarily as a "disorder of the NMJ". Despite the continuing ambiguity of sarcopenia etiology, it is clear that, at a minimum, age-dependent changes in the peripheral nerve and NMJ contribute to the muscle pathology in sarcopenia.

To test whether a young microbiome could reverse signs of aging, researchers took fecal samples from 3- to 4-month-old mice, the equivalent of young adults, and transplanted them into 20-month-old animals - ancient by mouse standards. The scientists fed a slurry of feces to the old mice using a feeding tube twice a week for 8 weeks. As controls, old mice received transplants from fellow old mice, and young from young. The first thing the team noticed was that the gut microbiomes of the old mice given young mouse microbes began to resemble those of the younger ones. The common gut microbe Enterococcus became much more abundant in old mice, just as it is in young mice, for example.

There were changes in the brain as well. The hippocampus of old mice - a region of the brain associated with learning and memory - became more physically and chemically similar to the hippocampus of young mice. The old mice that received young mouse poop also learned to solve mazes faster and were better at remembering the maze layout on subsequent attempt. None of these effects was seen in old mice given old mouse feces.

The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3-4 months) or old (19-20 months) donor mice into aged recipient mice (19-20 months). Transplant of a microbiota from young donors reversed aging-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.

Aging is a multifactorial phenomenon that affects virtually all cells and organ systems in the human body resulting in a progressive functional impairment and loss of homeostasis. One of the most dysregulated systems in aging is the immune system, with alterations in several biological and physiological processes that have significant repercussions on the overall well-being of the organism. The main roles of the immune system include the defense of the host against pathogens, the maintenance of homeostasis with clearance of dead cells and the regulation of healing processes. These activities are performed by specialized cells, that can activate general immune responses (innate immunity) or build specialized long-lasting defense against specific antigens (adaptive immunity). The progressive deterioration of the immune system affects both of these systems in elderly individuals, increasing susceptibility to infections, cancer, and inflammatory diseases, while delaying wound healing processes and reducing the ability to build an antibody response to some types of vaccination.

Indeed, the incidence of several infectious diseases, both bacterial and viral, increases with age and can be modeled based on immune system decline. In the same computational study, the authors showed that this is also true for cancer, indicating that the alteration of the immune system in aging may contribute to increased cancer incidence in the elderly. This work expands the scientific evidence on the relation between aging, immunity and cancer, but the exact ways in which they affect and influence each other remains debatable. Also autoimmune diseases have been investigated in the context of aging, with some evidence suggesting that they tend to be less frequent and less severe in elderly individuals, consistent with an overall decline in immune cell activity.

The dysfunctional immune system in aging has been associated with two processes defined as "immunosenescence" and "inflammaging". Immunosenescence, first proposed more than 40 years ago, is defined by the gradual deterioration of the immune system, which loses its ability to respond to infections and build effective long-lasting immune memory. More recently, studies have highlighted how several cell types of the innate and adaptive immune system undergo phenotypic changes during aging that impair their basic functions. At the beginning of 2000, a second phenomenon that affects the immune system in aging was proposed, termed inflammaging. While inflammatory processes are essential for the defense against foreign pathogens and clearance of dead and aberrant cells, their dysregulation and overactivation in the elderly causes a chronic inflammatory state that persists and promotes the development of inflammatory diseases associated with aging. These two processes are deeply interconnected, and can influence and maintain each other to create an imbalanced immune environment that is not only dysfunctional, but even acts as a driver for diseases development.

Individual differences are now starting to delineate a personalized way of aging that adds complexity to the investigation of deregulated processes. In this view, the identification of different immune ageotypes will help define subpopulations of elderly individuals with characteristic immune signatures and their longitudinal monitoring might help develop potential personalized anti-aging treatments. In this review, we report and discuss the contributions of different immune cells in aging and address the latest therapeutic options that have been proposed with the overall goal to rejuvenate or at least revitalize the immune system and slow down or even reverse immune aging.

The physiological function of resting, non-activated microglia in brain homeostasis is not well understood. Activated microglia may acquire paradoxical, opposite functions, either supporting regeneration and repair, or driving neuroinflammation. The triggers and mechanisms driving the cells towards one or the opposite functional direction are not well understood. However, inflammatory microglia can be harmful and destructive to the brain, whereas regenerative microglia may interfere with physiological brain remodeling processes.

Microglia are essential to the healthy brain, as they contribute to many brain functions and help sustain the physiological brain structure. Belonging to the innate immune system of the brain, microglia contribute to an immune response against any brain-invading agent, as well as following traumatic and neurovascular brain damage. They help with resolving tissue damage and support regeneration and restauration of structure and function. However, microglia may get out of control and out of balance resulting in augmenting brain damage or sustaining chronic pathologies like neuroinflammation and inducing or enhancing neurodegeneration. In such case, microglia may enhance brain aging.

The more we age, the more our immune system gets toward a more inflammatory status. The increased systemic inflammatory immune status also affects microglia, resulting in decreased physiological neuroregeneration and remodeling. The inflammatory status is certainly enhanced and accelerated through frequent or chronic viral infections. The increased and chronic inflammatory status in the brain may contribute to neurodegeneration due to increased neuronal cell death and reduced neurogenesis, reduced remodeling and irreparable damage to the neuronal network, resulting in an enhanced or accelerated brain aging process.

In the context of microglia and viral infection, most research has been done in HIV, where the association has been shown for neurocognitive decline. However, there is little information available about the cellular and molecular mechanisms that contribute to or influence the chronic HIV infection and corresponding involvement of microglia, which requires more future research. The same accounts for other viruses, including flaviviruses, human herpes viruses, and SARS-CoV-2.

Clearing the metabolic wastes and maintaining the fluid homeostasis are important for brain function. In most organs, the lymphatic network is responsible for the wastes clearance and fluid drainage. However, a hallmark of the brain is the absence of typical lymphatic structures. Due to the presence of blood-brain barrier (BBB), the movement of solutes and ions in the brain is strictly restricted. Cerebrospinal fluid (CSF) has been considered to be important for the exchange of water-soluble metabolites; however, its mechanisms remain largely unknown. In 2012 researchers reported the existence of the glymphatic system (GS) in the central nervous system (CNS), which is an alternative clearance system located in the perivascular space and aquaporin-4 (AQP4) dependent. Emerging evidence from human studies and rodent models suggests that the GS is crucial for maintaining brain health, and dysfunction of GS is closely associated with various neurological disorders, including aging, neurodegeneration, and acute brain injury. In parallel, the meningeal lymphatic vessels were discovered and demonstrated to participate in solutes transport and in immune surveillance.

Stroke, a major cause of death and disability, affects over 800,000 individuals annually. It has been well-recognized that the GS plays a crucial role in the pathophysiology of stroke, including brain edema, blood-brain barrier (BBB) disruption, immune cell infiltration, neuroinflammation, and neuronal apoptosis. Targeting the GS, therefore, has provided potential for the early risk assessment, diagnosis, prognosis, and therapeutic of stroke. In this review, we summarize the latest research progress in the GS, including the anatomy and function, the interaction with the meningeal lymphatic systems and the BBB, and the communication between astrocytes and other GS cellular components. We emphasize the role of the GS in pathophysiology of different stroke subtypes, especially the role of AQP4 in the pathophysiology of stroke.

It is well known that motor function, also commonly known as physical function or physical capability, declines with age, but rates of decline differ widely from person to person. And while studies show that decline in cognitive (mental) skills can emerge up to 15 years before death, it's not clear whether the same is true for physical abilities. To explore this further, researchers examined several measures of motor function for their associations with mortality over a 10 year period from around age 65.

Their findings are based on over 6,000 participants of the Whitehall II Study, which recruited participants aged 35-55 years in 1985-88 to look at the impact of social, behavioural, and biological factors on long term health. Between 2007 and 2016, participants underwent motor function assessments on up to three occasions. These included measures of walking speed, chair rise time, and grip strength, along with self-reported measures of functioning and difficulties with activities of daily living, such as dressing, using the toilet, cooking and grocery shopping.

After taking account of other potentially influential factors, the researchers found that poorer motor function was associated with an increased mortality risk of 22% for walking speed, 15% for grip strength, and 14% for timed chair rises, while difficulties with activities of daily living were associated with a 30% increased risk. These associations became progressively stronger with later life assessments.

Regular muscle strengthening exercises associated with aerobic activities can reduce cancer mortality, according to a systematic review of epidemiological studies. Workouts with squats, rowing, planks, weight training and so on can reduce the probability of dying from cancer by 14%. When these exercises are combined with aerobic activities, the benefit is even greater, potentially reducing mortality by 28%.

Epidemiological research using demographic data has shown that physical activity in general reduces the risk of breast, endometrial, stomach, throat, kidney, and bladder cancer. The present study found that muscle strengthening exercises can reduce the risk of kidney cancer by 26%. Statistically significant correlations were not found between muscle strengthening exercises and tumors primarily located in the colon, prostate, lung, pancreas, bladder, esophagus, and rectum, as well as melanoma, multiple myeloma, lymphoma, leukemia and cancers of the digestive system, owing to the limited number of studies.

The study also corroborated the recommendations of the World Health Organization (WHO) regarding regular aerobic exercise for adults: 150-300 minutes per week if moderately intense, 75-150 minutes of vigorous exercise, or an equivalent combination. The WHO also recommends twice-weekly strengthening exercises. The researchers analyzed 12 studies involving 11 cohorts and a control case, with participation by a total of 1,297,620 people, who were monitored in studies lasting between six and 25 years. The analysis suggested that strength training twice a week can protect against cancer.

Cellular senescence is a phenotype associated with limited replicative capacity and irreversible growth arrest of primary cells first described in the early 1960s. Senescent cells are characterized by specific phenotypical features that include enlarged and flattened cell morphology, enhanced lysosomal beta-galactosidase activity, increased expression of cell cycle inhibitors (p21Cip1/Waf1, p16Ink4A, p15Ink4B, and p53), and high metabolic activity including GSK3, AMPK, and mTOR pathways. In this regard, senescent cells differ from quiescent cells, which instead display a reversible cell cycle arrest and are characterized by a low metabolic status, a decrease in glucose uptake, and a reduction in mRNA translation.

Senescent cells arise in culture and in tissues following a variety of damaging insults such as DNA damage, oxidative stress, telomere shortening, mitochondrial dysfunction, and aberrant activation of oncoproteins. Besides the role of damaging agents, cellular senescence may also be induced by physiological stimuli including developmental and repair signals. Therefore, transiently-induced senescence plays a beneficial role in physiological events such as organogenesis, tissue homeostasis, and wound repair. Furthermore, the upregulation of cell cycle inhibitors in senescent cells plays a crucial role in their ability to suppress the development of cancer, thus senescence is considered as a tumor-suppressor phenotype.

Alongside the beneficial roles associated with transiently-induced senescence, the accumulation of senescent cells exerts detrimental effects on the functionality of tissues and organs. Indeed, the active metabolism of senescent cells drives the production of several members of cytokines, chemokines, growth factors, and proteases collectively known as senescence-associated-secretory-phenotype (SASP). Members of SASP include pro-inflammatory cytokines and chemokines such as IL-6, IL-8, and matrix degrading enzymes like MMP-1, MMP-3, and MMP-10. The release of such molecules in the cellular microenvironment induces a pro-inflammatory milieu, therefore leading to immune cell recruitment with the reinforcement of inflammation, paracrine senescence, tissue remodeling, and tissue degeneration.

Cellular senescence is one of the processes contributing to aging. With aging, senescent cells accumulate in the body tissues and associate with age-related pathologies, which include, among others, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), atherosclerosis, type 2 diabetes, tissue fibrosis, and cancer. Given the role of senescence in aging and age-associated diseases, there is a growing interest in developing approaches in order to target senescent cells. Much of this effort is focused on the development of strategies aimed at the clearance of senescent cells in vivo to reduce their accumulation and the subsequent alterations in tissue functionality. Here, we review the main approaches used to identify senescent cells in vitro and in vivo, with a focus on novel biomarkers of cellular senescence localized on the cell surface. We discuss the roles of surface proteins in SASP production and in the regulation of immune surveillance. Finally, we highlight the main therapeutic approaches that can be adopted to eliminate senescent cells in vivo by pharmacological and genetic approaches, with a focus on targeting the senescent surfaceome.

While insulin-like growth factor-1 (IGF-1) is a well-established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF-1 levels and clinical disease. We examined prospective associations of serum IGF-1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns.

First, IGF-1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF-1 are protected from disease, while older individuals with high IGF-1 are at increased risk for incident disease or death. Second, the association between IGF-1 and risk is generally U-shaped, indicating that both high and low levels of IGF-1 may be detrimental.

With the exception of a more uniformly positive relationship between IGF-1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age-associated diseases. These data suggest that IGF-1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.

The native tetrameric form of transthryetin (TTR) is a protective factor against oxidative stress. TTR is involved in reactive oxygen species (ROS) balance, extracellular matrix (ECM) remodeling, autophagy, apoptosis, reverse HDL cholesterol transport, proliferation, and angiogenesis under physiological conditions and in pathological disorders or stress-induced insults. The formation of TTR amyloid is induced by oxidative modification, aging, mutation, metal ions (including Ca2+), plasmin, and negatively charged polymers. The factors that compromise structural stability and lead to amyloid formation upon dysregulation may be responsible for improper/mislocated induction of TTR and result in cytotoxic TTR amyloid.

The contribution of TTR to cardiovascular and osteoarticular diseases is associated with the formation of TTR amyloid and calcification in the vascular and ligament tissues. Low levels of TTR in the plasma are observed in CVDs and the majority of osteoarticular disorders. It is difficult to determine whether changes in the processes or TTR levels correspond to a cause or a consequence of amyloid formation and whether adverse effects observed in amyloid-induced diseases are a consequence of amyloid overload or a loss of the protective functions of TTR.

Unaggregated/native and aggregated/amyloid TTR forms are interconnected in the following loops. Vicious cycle 1, oxidative stress: oxidative modifications lead to TTR destabilization and pathological amyloid, which increases oxidative stress. Properly folded TTR is a factor that suppresses oxidative stress, inhibits intracellular Ca2+ influx, ROS production, membrane permeabilization, apoptosis, and autophagy, and promotes the assembly of oligomeric proteins into larger, less toxic aggregates. Vicious cycle 2, Ca2+: TTR amyloid is formed in situ in response to high Ca2+ concentration, which, in turn, promotes TTR destabilization and amyloid deposition, which entraps more Ca2+. Vicious cycle 3, inflammation: plasmin or other factors induce the formation of TTR amyloid. Amyloid deposits cause plasmin activation and induce inflammation, which, in turn, promotes amyloid formation. Vicious cycle 4, lipids: cholesterol and anionic phospholipids bind TTR and promote TTR aggregation. On the other hand, aggregated TTR alters membrane fluidity and induces cytotoxic effects, upregulating TTR aggregation.

For decades, researchers have known that the immune system not only plays a key role in battling cancers through the direct action of killer T cells and other components, but also opposes these efforts through cells known as regulatory T cells (Tregs). These Tregs help to regulate the immune response by preventing various immune cells from becoming overactive and causing autoimmune diseases. However, they also accumulate in tumors, shielding them from immune attack.

Tregs maintain a balance of two proteins on their surfaces - CTLA-4 and CD47 - that respectively broadcast "eat me" and "don't eat me" signals to phagocytes that keep Tregs in check. Various immunotherapies have sought to boost the "eat me" signal or decrease the "don't eat me signal" to reduce Tregs in tumors. However, each strategy has drawbacks: Increasing the "eat me" signal has systemic effects that spur autoimmunity, while decreasing the "don't eat me" signal has only shown promise for treating blood cancers, such as leukemias.

Searching for a new way to deplete Tregs, researchers created a two-arm molecule that simultaneously increases the "eat me" signal while blocking the "don't eat me" signal to prompt phagocytes to consume those immune suppressive cells. When it was injected into mouse models of colon cancer, they found that it preferentially depleted Tregs in tumors without affecting those in the rest of the body, sparing the animals from treatment-induced autoimmune disease. However, dosing these animals with equivalent, separate amounts of the "eat me" booster and "don't eat me" blocker had systemic autoimmune side effects, suggesting that combining them within one molecule is key to reaching Tregs in tumors. As the number of Tregs decreased with treatment, the animals' tumors shrank significantly. This strategy also worked in mice carrying human lung cancer tumors, suggesting that it could be viable in human patients.

One of the distinctive features of aging is the progressive loss of muscle mass and physical function, collectively known as sarcopenia. In parallel with the progressive loss of muscle function, mitochondrial respiratory activity in human skeletal muscle has been shown to decrease with advancing age in healthy men and women. Furthermore, protein levels of the mitochondrial master regulator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) were found to correlate with walking speed in healthy older adults. Some preclinical studies indeed suggest that the reduction in muscle mitochondrial function may underlie the decline in muscle health during aging. Therefore, it is tempting to speculate that augmenting mitochondrial function could be a potential strategy to counteract aging-associated decline in physical function.

Although some human studies have addressed age-related alterations in muscle mitochondrial function in relation to the decline in skeletal muscle function, the available data in humans is scarce and the few available studies often focus on either the decline in muscle function or concentrate primarily on the mitochondrial alterations. Additionally, the age-associated decline in mitochondrial function is not completely attributable to aging per se and may also be explained, in part, by an age-related decline in physical activity (PA). Decreased PA can adversely affect mitochondrial capacity.

To delineate these relationships, we conducted a cross-sectional study with detailed phenotyping in groups of young versus older human participants, with a range in oxidative capacity and physical function. The first aim of the study was to assess if mitochondrial function is reduced in older compared to young participants with a similar level of habitual PA, and to examine how mitochondrial function relates to muscle function.

Aging was associated with a decline in mitochondrial capacity, exercise capacity and efficiency, gait stability, muscle function, and insulin sensitivity, even when maintaining an adequate daily physical activity level. Our data also suggest that a further increase in physical activity level, achieved through regular exercise training, can largely negate the effects of aging. Finally, mitochondrial capacity correlated with exercise efficiency and insulin sensitivity. Together, our data support a link between mitochondrial function and age-associated deterioration of skeletal muscle.

To come up with a number for total daily energy expenditure, researchers relied on the "doubly labeled water" method. It's a urine test that involves having a person drink water in which the hydrogen and oxygen in the water molecules have been replaced with naturally occurring "heavy" forms, and then measuring how quickly they're flushed out. Scientists have used the technique to measure energy expenditure in humans since the 1980s, but studies have been limited in size and scope due to cost. So multiple labs decided to share their data and gather their measurements in a single database, to see if they could tease out truths that weren't revealed or were only hinted at in previous work.

Energy needs shoot up during the first 12 months of life, such that by their first birthday, a one-year-old burns calories 50% faster for their body size than an adult. "Something is happening inside a baby's cells to make them more active, and we don't know what those processes are yet." After this initial surge in infancy, the data show that metabolism slows by about 3% each year until we reach our 20s, when it levels off into a new normal.

Midlife was another surprise. Perhaps you've been told that it's all downhill after 30 when it comes to your weight. But while several factors could explain the thickening waistlines that often emerge during our prime working years, the findings suggest that a changing metabolism isn't one of them. In fact, the researchers discovered that energy expenditures during these middle decades - our 20s, 30s, 40s and 50s - were the most stable.

The data suggest that our metabolisms don't really start to decline again until after age 60. The slowdown is gradual, only 0.7% a year. But a person in their 90s needs 26% fewer calories each day than someone in midlife. Lost muscle mass as we get older may be partly to blame, since muscle burns more calories than fat. But it's not the whole picture. "We controlled for muscle mass. It's because their cells are slowing down."

The characteristics of chronic kidney disease (CKD) are similar to those of the aging process; therefore, it has been hypothesized that CKD promotes premature aging associated with related diseases. Furthermore, chronic diseases usually observed in aging, such as cardiovascular disease (CVD), inflammation, vascular calcification, mineral, and bone disorders, and chronodisruption (chronic alteration of circadian rhythms), are markedly frequent in patients with CKD.

CVD is the most clinically relevant comorbidity associated with CKD. The coexistence of both diseases could be explained by the following: (1) patients with CKD have a higher prevalence of non-traditional cardiovascular risk factors, (2) many cardiovascular risk factors exacerbate CKD progression, and (3) CKD itself can be considered a risk factor for CVD. According to 2013 data from the U.S. Renal Data System, an estimated 43% and 15% of patients with CKD experience heart failure and acute myocardial infarction in their lifetime (versus healthy persons: 18.5% and 6.4%, respectively).

The development of CVD in patients with CKD is due primarily to endothelial dysfunction. Endothelial cells in patients with renal disorders experience premature senescence due to received stress signals, which may lead to apoptosis. Under physiological conditions, endothelial cells have a non-adherent and anticoagulant surface; however, molecules expressed on the surface of damaged endothelial cells may be altered, increasing cell adhesion capacity. Platelets bind to the damaged surface, triggering the onset of coagulation with consequent inflammation and thrombosis, thereby causing cardiovascular accidents.

Several factors, such as inflammation, oxidative stress, primary diseases such as hypertension or diabetes, and hyperlipidemia, contribute to endothelial deterioration in CKD. Another example is hyperphosphatemia, which is present in many patients with renal disorders. High phosphate concentrations increase oxidative stress and reduce the concentration of nitric oxide, which the endothelial cells release to relax and avoid the rigidity of the arteries and regulate endothelial permeability.