Fight Aging! Newsletter, October 17th 2016

Scientists have discovered a new way to look for ageing cells across a wide range of biological materials; the new method will boost understanding of cellular development and ageing as well as the causes of diverse diseases. Frustrated by the limitations of commercially available biomarkers the researchers have developed a universally applicable method to assess senescence across biomedicine, from cancer research to gerontology. Cellular senescence is a fundamental biological process involved in every day embryonic and adult life, both good - for normal human development - and, more importantly to researchers, dangerous by triggering disease conditions. Up to now available senescence detecting biomarkers have very limited and burdensome application. Therefore, a more effective, precise and easy-to-use biomarker would have considerable benefits for research and clinical practice. "The method we have developed provides unprecedented advantages over any other available senescence detection products - it is straight-forward, sensitive, specific and widely applicable, even by non-experienced users. In addition to helping researchers make significant new breakthroughs into the causes of diseases - including cancer - through more effective understanding of senescence in cells, the new process will also aid the impact of emerging cellular rejuvenation therapies. By the better identification - and subsequently elimination of - senescent cells, tissues can be rejuvenated and the health span extended."

The research group had previously discovered that cell senescence was effectively induced by using low concentrations of anticancer drugs on cancerous cells. In anticancer treatment, drugs are carried to the cancerous tissue via the bloodstream. The researchers predicted that differences in concentrations of the anticancer drugs would arise based on the distance of the cells from the blood vessels, and so even in the normal cancer treatment process senescent cells would emerge. Therefore, if we simultaneously administer a medicine that inhibits cell senescence during standard cancer treatment, there is the potential for a dramatic increase in treatment effectiveness. Previously the research group found that if cancerous cells are treated with a low concentration (10 μM) of the anticancer drug etoposide this induces cell senescence, and if they are treated with a high concentration of the drug (100 μM) this induces apoptosis. For this research, they treated cancerous cells under three different conditions: A) with no etoposide; B) with a low dose of etoposide (10 μM); and C) with a high dose of etoposide (100 μM). They then used DNA microarrays to identify the genes in which a rise in transcription levels could be observed.

They predicted that genes which showed increased expression in response to treatment B were mainly related to cell senescence, genes expressed in response to C were mainly those involved in apoptosis, and among the genes which specifically showed increased expression in B compared to C would be genes that play an important role in implementing cell senescence. There were 126 genes where three times as much expression was recorded under treatment B compared to A, and 25 genes that showed twice as much expression in B compared to C. These 25 genes are expected to express specifically in senescent cells since the other factors caused by DNA damage are removed, and researchers confirmed that the genes involved in causing cell senescence were among them. If we can develop a drug that targets and regulates the activity of the genes that control senescence identified in this research, by administering it together with conventional anticancer treatment we can limit the emergence of senescent cells and potentially increase the effectiveness of cancer treatment. Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells. This means that drugs which control cell senescence could have potentially large benefits for the development of anti-aging medication products.

Cell senescence can be defined as the irreversible cessation of cell division of normally proliferating cells. Human cells become senescent from progressive shortening of telomeres as cells divide, stress or oncogenes. Primarily an anti-tumour mechanism, senescent cells accumulate with age in tissues and have been associated with degeneration and ageing of whole organisms. Many proteins have been linked to cell senescence as biomarkers and as causal drivers. To facilitate studies focused on cell senescence, we developed CellAge, a database of genes associated with cell senescence. Our manually-curated data is based on gene manipulation experiments in different human cell types. A gene expression signature of cellular senescence will also be made available in due course. CellAge is in the beta phase of development and therefore still being improved and expanded. Collaborations and contributions are welcomed, please contact us if you wish to be involved.

Cardiac muscle cells grown from the stem cells of one macaque monkey can be used to regenerate the hearts of other macaques. The transplanted cells improved the heart's ability to contract after an induced heart attack and integrated with no sign of rejection by the recipient's immune system. However, the recipient's heart did suffer from an irregular heart beat in the first four weeks after the transplant, but this passed and was non-lethal. Researchers used cardiac muscle cells derived from induced pluripotent stem cells (iPSC-CMs) from a donor instead of the patient's own cells. Donor cells are considerably easier to manufacture but increase the risk of being rejected by the recipient's immune systems. The scientists overcame this by matching a surface protein on the donor and recipient's cells that is used by the immune system to recognize foreign cells.

"We found that monkey iPSC-CMs or cardiac muscle cells derived from induced pluripotent stem cells survived in the damaged monkey heart and electrically coupled with the host heart. In addition, the heart's ability to contract was partially recovered by the transplantation. We had a hard time handling monkey iPS cells. Unlike human iPS cells, they are somewhat tricky. The condition of iPS cells are critical for generating high purity cardiac muscle cells. Also, it took a long time to get grafted cardiac muscle cells to survive in the recipients. In addition to daily treatments of immunosuppressant drugs, we made sure the surface protein major histocompatibility complex (MHC), which is used by the immune system to recognize foreign cells, was carefully matched on the donor and recipient's cells. Human embryonic stem cell-derived cardiac muscle cells have already been used in clinic as a new therapy for post myocardial infarction (MI) heart failure. But I think it will take at least a couple of years for this treatment to become more widely-used."

Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, few immunological studies have been carried out with iPSCs. Here we describe an allogeneic transplantation model established using the cynomolgus monkey (Macaca fascicularis), the MHC structure of which is identical to that of humans. Fibroblast-derived iPSCs were generated from a MHC haplotype (HT4) homozygous animal and subsequently differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of iPSC-CMs.

The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection in monkeys treated with clinically relevant doses of methylprednisolone and tacrolimus, and showed electrical coupling with host cardiomyocytes. Additionally, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks after transplantation; however, the incidence of ventricular tachycardia was transiently, but significantly, increased when compared to controls. Collectively, our data demonstrate that allogeneic iPSC-CM transplantation is sufficient to regenerate the infarcted non-human primate heart; however, further research to control post-transplant arrhythmias is necessary.

Research shows that scanning ultrasound prevented degeneration of cells in the brains of healthy mice. "We found that, far from causing any damage to the healthy brain, ultrasound treatments may in fact have potential beneficial effects for healthy ageing brains. In a normal brain the structure of neuronal cells in the hippocampus, a brain area extremely important for learning and memory, is reduced with age. What we found is that treating mice with scanning ultrasound prevents this reduction in structure, which suggests that by using this approach we can keep the structure of the brain younger as we get older. We are currently conducting experiments to see if this preservation of the brain cell structure will ameliorate reductions in learning and memory that occur with ageing." In the next stage of research, the team will test the effect of ultrasound on the brain structure and function of older mice.

Recently, our group has reported that repeated scanning ultrasound (SUS) treatments reduced the amyloid plaque pathology in a transgenic mouse model of Alzheimer's disease (AD) and improved hippocampal-dependent spatial memory performance by activating brain-resident microglia. In this approach, ultrasound was combined with microbubbles to disrupt the blood-brain barrier (BBB) which is achieved by mechanical interactions between the microbubbles and the blood vessel wall as pulsed focused ultrasound is applied, resulting in cycles of compression and rarefaction of the microbubbles. This leads to a transient disruption of tight junctions and the uptake of blood-borne factors by the brain, which are likely to have a role in the activation of microglia that were found to take up amyloid into their lysosomes.

However, the short- and long-term effects of SUS treatment on individual neuronal action potential (AP) firing and dendritic morphology have not been investigated. To address this issue, we evaluated the physiological effects of both a single and multiple SUS treatments on short- and long-term neuronal excitability, dendritic morphology and dendritic spine densities in the CA1 region of the hippocampus of wild-type mice. This allowed us to determine the effect of different SUS treatments in a non-disease state system before eventually moving to a more complicated disease model, where alterations in neuronal function are already present at an early age. For example, reductions in dendritic spine density, AP firing, synaptic activity and long-term potentiation (LTP) have all been reported to occur in amyloid-depositing mouse models of AD.

In our study using wild-type mice, we found that the different SUS treatment regimes had no deleterious effect on neuronal function or morphology. In addition to this we made the interesting observation that repeated SUS treatments prevented reductions in the dendritic complexity and length of CA1 pyramidal neurons that occur in age-matched sham-treated wild-type mice over the course of three months, while a reduction in dendritic spine density was not halted. Taken together, these findings suggest that multiple SUS treatments ameliorate a reduction in the total number of dendritic spines per neuron. A more extensive follow-up study will determine, whether SUS treatments improves cognition in aging mice and what the underlying mechanism is of such an effect.

Age-associated reductions in the structure of neuronal dendritic trees have previously been reported in a range of brain areas and species. However, our understanding of changes in dendritic tree arborization in the hippocampus is less advanced, where both increases and decreases in CA1 pyramidal dendritic length and complexity have previously been reported. While a number of differences exist between these reports and the current work, perhaps the most important is the duration of ageing over which changes in dendritic tree structure was quantified (approximately 1.5 years versus 3 months in the current study). This is a limitation of the current study when evaluating changes in dendritic structure associated with ageing. Further experimentation will be required to assess changes in dendritic tree structure over longer time periods. Despite this, it is evident that multiple SUS treatments are able to prevent reductions in dendritic structure.

Also, the question of how SUS preserves dendritic structure remains to be determined. One possibility is that microglia may play a role, because SUS treatment has previously been reported to activate this cell-type in mouse models as well as in wild-type mice. Microglia constantly probe their local environment and secrete factors that alter neuronal signalling. During activation they can also modify synaptic connections, the key mediators of learning and memory, by increasing the expression of neurotrophins such as brain-derived neurotrophic factor (BDNF). In fact, a recent study has reported that microglia mediate synapse loss at an early time-point in Alzheimer's disease mouse models. One possible mechanism for the neurotrophic effect of SUS may therefore be the delivery of endogenously circulating neurotrophic factors from the blood to the brain. Furthermore, ultrasound waves by themselves, without the need for BBB opening, may also contribute to the observed preservation of dendritic structure, as increased BDNF expression has been reported following ultrasound application. Other neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) have also been linked to improve memory performance in rats following ultrasound treatment.

Using a mouse model of tauopathy that produces a mutated form of human tau protein, researchers correlated memory deficits with the presence of a fragment of the tau protein. The tau fragment, which is produced when caspase-2 cuts the full-length tau protein at a specific location, was also found at higher levels in the brains of Alzheimer's disease patients compared to healthy individuals of the same age. While the standard hallmark of tauopathies is the appearance in brain tissue of large tangles of abnormal tau protein, it has recently become less clear whether the tangles of tau are actually causing cognitive decline. "In the past, many studies focused on the accumulation of tangles and their connection to memory loss, but the more we learn, the less likely it seems that they are the cause of disease symptoms. The pathological fragment of tau that we have identified resists forming tangles and can instead move freely throughout the cell. Therefore, we decided to look for other mechanisms that could affect synaptic function."

The researchers used fluorescent labeling to track and compare the behavior of normal and mutated tau in cultured neurons from the rat hippocampus, the brain region most associated with learning and memory. Unlike normal tau, both mutated tau and the short fragment produced when caspase-2 cuts tau were primarily found within structures called dendritic spines, where neurons receive inputs from neighboring cells. The overabundance of mutated tau, including the caspase-2-produced fragment, caused disruptions in synaptic function in the spines. The impact on synapses was specific, with no observed effects on the overall structure or survival of the neurons. "It appears that abnormally processed tau is disrupting the ability of neurons to properly respond to the signals that they receive, producing memory deficits independent of tangle formation. Because this effect is occurring without cell death or a loss of synapses, we have a better chance of intervening in the process and hopefully reversing symptoms of the disease."

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

Industry leading nutritechnology company L-Nutra has announced the release of ProLon, a groundbreaking 5 days per month only natural plant based meal program that nourishes the body while convincing it that it is fully fasting. This is the first time in history that 'Fasting with Food' is possible and is therefore called the Fasting Mimicking Diet (FMD). Developed at the Longevity Institute of the University of Southern California (USC) and under the sponsorship of the National Institute for Aging and the National Institute of Health, ProLon induces the body to protect itself and rejuvenate in response to 5 consecutive days of fasting.

In the latest clinical trial conducted at USC's Longevity Institute, 100 participants on 3 cycles of ProLon (5 days only per month over a 3-month period) showed statistically significant improvements on various health metrics: decrease in body fat; decrease in body weight; preservation of bone density; reduction in fasting glucose and insulin resistance; optimization of cholesterol and triglyceride levels; decrease in IGF-1 (aging marker); decrease in C-reactive protein; elevated mesenchymal/progenitor cells (rejuvenation marker). This 'fasting with food' program features meals ranging from 770 to 1,100 calories per day.

Researchers have found clues to the causes of age-related hearing loss. The ability to track and understand speech in both quiet and noisy environments deteriorates due in part to speech processing declines in both the midbrain and cortex in older adults. Thirty-two native English-speaking volunteers with clinically normal hearing were assigned to two groups: younger adults (average age, 22) and older adults (average age, 65). The research team measured the volunteers' speech comprehension using the Quick Speech-in-Noise (QuickSIN) test. The researchers also gave the volunteers an electroencephalogram, which measured mid-brain activity, and a magnetocephalogram to measure cortical activity. For both groups, the researchers calculated the listeners' ability to comprehend speech in quiet settings and environments with more than one person talking. Background noise was delivered in four distinct signal-to-noise ratios (SNR), which measures signal strength (i.e., the primary talker) relative to background noise (i.e., the competing reader).

The researchers found that the older group had more trouble tracking speech than the younger group in both quiet and noisy environments across all SNRs. The older adults took more time to process several acoustic cues, such as accuracy of speech, and also scored lower on the QuickSIN test for speech comprehension in noise. Deficits from aging were also seen neurally, both in midbrain and cortex, according to the researchers. These results suggest that age-related problems with understanding speech are not only due to the inability to hear at certain volumes but also occur because the aging brain is not able to correctly interpret the meaning of sound signals.

The older adults gained significant benefit in focusing on and understanding speech if the background is spoken by a talker in a language that is not comprehensible to them (i.e. a foreign language). The results suggest that neural processing is strongly affected by the informational content of noise. Specifically, older listeners' cortical responses to the attended speech signal are less deteriorated when the competing speech signal is an incomprehensible language than when it is their native language. Conversely, temporal processing in the midbrain is affected by different backgrounds only during rapid changes in speech, and only in younger listeners. Additionally, cognitive decline is associated with an increase in cortical envelope tracking, suggesting an age-related over (or inefficient) use of cognitive resources that may explain difficulty in processing speech targets while trying to ignore interfering noise.

Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing.

Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.

Because Alzheimer's disease (AD) is the leading cause of dementia, many people use the two terms interchangeably. But inadequate blood flow to the brain due to microinfarcts, mini-strokes, or strokes is a hallmark of a disease called Vascular Cognitive Impairment and Dementia (VCID). VCID is the second most common cause of dementia, and the two are not mutually exclusive - researchers estimate that 40-60% of Alzheimer's disease patients also have VCID. A paper recently published reports that a certain form of immunotherapy targeted to Alzheimer's patients may be ineffective when that patient also has VCID. "These findings are important in that they provide a possible explanation for why clinical trials of anti-Aβ immunotherapy for Alzheimer's disease have been historically unsuccessful. If up to 40 percent of people with Alzheimer's also have VCID, treatment candidates that target only the AD physiology won't be effective in those patients. It's like treating only half the disease."

Most researchers agree that the formation of brain plaques containing amyloid β (Aβ) peptides is an initial step in the development of Alzheimer's disease, which has led to a race to identify and test treatments that reduce the levels of these plaques. Anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain, has been a leading approach. While these drugs showed promise in animal studies, clinical trials have failed to show similar benefits in human patients. Without a suitable animal model, testing the vascular dementia hypothesis would not have been possible. Fortunately, the research team had already developed an innovative model of combined AD and VCID. Using this mouse model, together with its parent model of AD without VCID, scientists evaluated the ability of an anti-Aβ antibody to enhance cognitive capabilities in both models. While Aβ levels were reduced in both groups, cognitive function was not improved in the groups with combined AD and VCID. "The failure of anti-Aβ immunotherapy in the mixed AD-VCID model suggests that both disease processes have to be treated to have a successful outcome. The missing link has been that our animal models usually possess the hallmarks of only one disease, which has led to failure of successful translation to clinic."

One particular protein is the final executioner of events that result in the death of brain cells during stroke, researchers report. This finding could ultimately lead to new ways to protect against brain damage. Researchers discovered that the protein, macrophage migration inhibitory factor (MIF), breaks the cell's DNA, resulting in brain cell death. The study outlines three possible ways to manipulate MIF to protect brain tissue during a stroke - and possibly in other brain-damaging conditions such as Alzheimer's, Parkinson's, and Huntington's diseases, although this study examined only stroke. Researchers screened thousands of human proteins to find 160 that could be the culprits behind stroke-induced cell death. Eventually, the researchers were able to narrow the field to just one - MIF, a protein long known for its roles in immunity and inflammation.

The MIF finding is the final piece in a puzzle that researchers have been carefully assembling for years to reveal the process by which brain cells die. Despite their very different causes and symptoms, brain injury, stroke, and Alzheimer's, Parkinson's, and Huntington's diseases have a shared mechanism involving a distinct form of "programmed" brain cell death called parthanatos, researchers said. The name comes from the personification of death in Greek mythology, and PARP, an enzyme involved in the cell death process. "I can't overemphasize what an important form of cell death it is; it plays a role in almost all forms of cellular injury." The researchers are working to identify chemical compounds that could block MIF's actions and possibly protect brain cells from damage.

Interventions that extend longevity in model laboratory organisms have proliferated. Traditionally, such interventions have been assumed to retard aging itself based on their ability to increase mean and maximum lifespan. The emphasis on longevity metrics alone made some sense in that longevity seemingly provides an unambiguous endpoint that has been assumed to be necessarily correlated with a general age-related physiological decline. While this may often be the case, it is not necessarily so. Indeed, human females live longer lives than males, but also suffer greater age-related morbidity by a number of measures. In laboratory species, long-lived worm genotypes are often outcompeted by shorter-lived genotypes and some evidence suggests that by a number of measures some long-lived worm genotypes are less healthy than the standard genotype even relatively early in life. As a major goal of basic aging research is to develop interventions that will enhance and prolong health in humans, it would be beneficial to the field to determine for all model organisms, which interventions extend health and which extend only life.

Because efforts to develop a cognate battery of tests to assess healthspan in mice and other model organisms have met with varying degrees of success we have taken a different approach. We feel that important indicators of health that can be commonly addressed in humans and in mice can be roughly categorized as those associated with age-related decreasing strength and mobility and those associated with decreasing cognitive capabilities. To this end, we present here an analysis of age-related change in commonly measured, noninvasive parameters associated with age-related changes in energetics, strength and mobility in the commonly used C57BL/6 mouse strain, and we determined to what extent these health parameters were associated with premature death. We measured age-related changes in healthspan in male and female mice assessed at 4 distinct ages (4 months, 20 months, 28 months and 32 months). Correlations between health parameters and age varied. Some parameters show consistent patterns with age across studies and in both sexes, others changed in one sex only and others showed no significant differences in mice of different ages. Few correlations existed among health assays, suggesting that physiological function in domains we assessed change independently in aging mice. With one exception, health parameters were not significantly associated with an increased probability of premature death. Our results show the need for more robust measures of murine health and suggest a potential disconnect between health and lifespan in mice.

Heart failure occurs when heart function is reduced making it no longer able to pump enough blood to body. Patients with severe heart failure have a very poor prognosis, with a five-year survival rate of 50-60% despite advances in modern medicine and medical technology. Researchers found that cardiac muscle cells that were from heart failure patients, were aged cells, or were under the stress of high blood pressure had increased production and secretion of the protein ANGPTL2. The research team previously reported that excessive secretion of the ANGPTL2 protein by aged or stressed cells causes chronic inflammation and promotes the development of lifestyle-related diseases such as atherosclerotic disease, obesity, diabetes, or cancer. ANGPTL2 is also related to heart failure. Excessive ANGPTL2 secretions by cardiac muscle cells impair important functions, such as intracellular calcium concentration regulation and energy production, that help maintain the contractile force of the heart. On the other hand, moderate exercise reduces the production of ANGPTL2 in cardiac muscle cells which helps keep the heart healthy.

"We found that ANGPLT2 is significantly involved in heart failure. Among knockout mice that could not produce the protein, the development of heart failure was suppressed in a manner similar to moderate exercise. Furthermore, we genetically engineered a non-pathogenic virus which was designed to infect cardiac muscle cells and reproduce a special RNA molecule that inhibited the production of the ANGPTL2 protein." This new gene therapy in the heart failure mouse model was successful in suppressing ANGPTL2 production in cardiac muscle cells thereby reducing the pathological progression of heart failure. Additionally, in cardiac muscle cells that were differentiated from human induced pluripotent stem cells, the suppression of ANGPYL2 promoted calcium concentration regulation and enhanced energy production. It is considered that the newly developed gene therapy may also be effective for human heart failure patients. Current treatment for heart failure is mainly symptomatic. The gene therapy developed here is expected to become a fundamental treatment that corrects the mechanism of reduced heart function itself.

SIWA Therapeutics today reports results of its recent in vivo preclinical study which showed that its monoclonal antibody for removing senescent cells, SIWA 318, significantly inhibited tumor metastasis. Importantly, there were no observable adverse effects from the treatment and no increase in tumor growth over the control group. "These results suggest that the removal of senescent cells may become a therapeutic approach against metastatic cancers. Based on data we and the rest of the scientific community have generated over the last several years, the evidence is clearly mounting that senescent cells are causally implicated in the manifestation and progression of many diseases including cancer metastasis."

Amyloidosis is a protein conformational disorder in which amyloid fibrils accumulate in the extracellular space and induce organ dysfunction. Recently, two different amyloidogenic proteins, transthyretin (TTR) and apolipoprotein A-I (Apo A-I), were identified in amyloid deposits in knee joints in patients with knee osteoarthritis (OA). However, clinicopathological differences related to those two kinds of amyloid deposits in the knee joint remain to be clarified. Here, we investigated the clinicopathological features related to these knee amyloid deposits associated with knee OA and the biochemical characteristics of the amyloid deposits.

We found that all of our patients with knee OA had amyloid deposits in the knee joints, especially in the meniscus, and those deposits were primarily derived from TTR and/or Apo A-I. Some patients with knee OA, however, had unclassified amyloid deposits. One of our interesting observations concerned the different effects of aging on each type of amyloid formed. The frequency of formation of ATTR deposits clearly increased with age, but that of AApo A-I deposits decreased. Furthermore, we found that ∼16% of patients with knee OA developed ATTR/AApo A-I double deposits in the meniscus. Amyloid deposition may therefore be a common histopathological feature associated with knee OA. Also, aging may induce ATTR formation in the knee joint in elderly patients with knee OA, whereas AApo A-I formation may be inversely correlated with age.

It's certainly a good bet that applying rejuvenation biotechnologies to remove, repair, and replace other kinds of aging damage will in some ways make us less vulnerable to cancer. Notably, ablating senescent cells would eliminate the "senescence-associated secretory phenotype" (SASP), which promotes the growth and invasiveness of cancers in several ways, including stimulating early-stage cancer cells to continue replicating, encouraging the growth of new blood vessels needed by cancer cells to supply themselves with fuel and oxygen, and breaking down the physical barriers that prevent them from metastasizing, which is when most cancers become deadly. Also, rejuvenating the aging immune system (by eliminating the dysfunctional T-cells that accumulate with age and rebuilding the atrophied thymus gland) will restore the body's ability to suss out and eliminate cancers as they emerge. But it's also clear that deploying these other rejuvenation biotechnologies won't be enough to eliminate cancer altogether, and that must be our ultimate goal.

First, we already know that cancers can evolve multiple mechanisms to avoid being hit or destroyed by antibodies and immunological factors, and the longer a person lives with proto-cancerous cells (even in the presence of a healthy, young immune system), the longer those cells have to develop ways to evade such an immune system. This is one of the reasons that cancer is an age-related disease, despite the fact that young people can and do certainly get cancer, and despite the fact that many late-life cancers originate with mutations that arise in the body decades earlier. More importantly, perhaps, there is good reason to worry that otherwise-rejuvenated tissues in a body that is still vulnerable to the core processes of cancer may actually become more vulnerable to cancer than they would be under "aging as usual." Consider the following contrasting scientific findings.

On the one hand, it has been shown in animal experiments that when you transplant a pre-formed cancer into an old host, it usually grows more quickly than the same cancer does when transplanted into a young one. This is as you'd expect from things that make the aged host more vulnerable to cancer: senescent cells make it easier for the implanted cancer to take root and spread, and a flagging immune system is less able to root out the invader. On the other hand, when you infect mice with a virus that can cause new cancers to form, it is actually less likely to happen in an old mouse than in a young one - and the tumors that do form grow more slowly, despite the weakened immune system and burden of senescent cells in the older animal. This strongly suggests that something about biological aging itself eventually makes our tissues less prone to forming cancers.

Consistent with this, consider the phenomenon of people (and mice) with mutations in DNA repair genes that cause them to accumulate mutations more rapidly than the rest of us. These people develop an "old" burden of potentially cancer-causing mutations in a body that is otherwise still young. This would be similar to having an otherwise-rejuvenated body in which the problem of age-associated mutations had not been solved by a specific rejuvenation biotechnology. Such people develop what are often very aggressive cancers at much younger ages than is typical in the general population. This suggests that once the mutations needed to form a cancer take hold, even an otherwise-young body is unable to hold the invasion back. Thus, rejuvenating the body will reduce the risk of some cancers (notably, by reversing immunosenescence, clearing out senescent cells, and restoring the structural integrity of the extracellular matrix of our tissues). In other ways, however, rejuvenation could restore the host tissues' intrinsic vulnerability to forming new cancers, and to that extent make cancer more of a risk: all those fresh, proliferation-competent cells, and a restored signaling environment full of growth factors.

As we age, our metabolism slows and our immune system runs out of steam. Older people are more likely to have severe cold and flu symptoms, probably because they have fewer fresh immune cells left. And a slower metabolism means that glucose stays in the blood stream for longer after eating a meal. Over time, high blood sugar levels can damage organs. But experiments in mice suggest that transplanting organs from a younger individual could reverse these changes. Researchers removed the ovaries of 10 mice that were 12 months old and had gone through oestropause, a transition similar to the human menopause. They replaced these with ovaries taken from 60-day old mice - roughly equivalent to people in their early 20s in terms of ageing.

Four months later, the researchers assessed the mouse immune systems. The numbers of immune cells that respond to new infections - called naive T-cells - tend to decline with age, and had already fallen in these mice before surgery. Between the ages of 6 months (before the operation) and 16 months, the number of naive cells in these mice rose by around 67 per cent. Cell counts fell by 80 per cent in untreated mice over the same period. To test metabolism, researchers injected the mice with glucose and measured how long it took for their blood sugar levels to return to normal. The mice with young ovaries removed glucose from their blood faster than untreated mice. The findings build on the team's previous work, which found that mice transplanted with young ovaries in middle age live about 40 per cent longer than their peers, and have healthier looking hearts too. How young ovaries might exert these benefits remains something of a mystery. One theory is that the hormones produced by the eggs inside these ovaries are responsible. But when researchers killed all the eggs inside young ovaries before transplanting them into another set of older mice, they still saw the same benefits. The researchers theorize that some other kind of cell inside the ovary might be responsible for the rejuvenation.