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- A Rate of Living Approach to the Concept of Programmed Aging
- A Look Back at 2019: Progress Towards the Treatment of Aging as a Medical Condition
- Senolytic Therapies as Preventative Medicine for Glaucoma
- Better Characterizing the Clonal Expansion of Somatic Mutations in Aging Tissues
- Building a Biomarker of Aging from Frailty Measures
- A Discussion of Relaxin as a Possible Treatment for Heart Failure
- Autophagy as a Common Denominator of Age-Slowing Interventions in Animal Models
- A Fourfold Greater Risk of Cardiovascular Mortality in Women with Poor Fitness
- Smooth Muscle Cells in Age-Related Vascular Degeneration and Calcification
- Intermittent Fasting is Beneficial in Humans
- Controlling Hypertension Reduces Dementia Risk, but Only if Done Early
- Impairment of the Ubiquitin Proteasome Pathway in Aging and Neurodegeneration
- Disruption of Mitochondrial Dynamics in Cardiovascular Disease
- Physical Activity Correlates with Reduced Mortality
- More Aggressive Blood Pressure Control Reduces the Structural Damage Done to the Brain
A Rate of Living Approach to the Concept of Programmed Aging
A vocal minority of gerontologists consider aging to be a genetic program. In their view, changes in regulation of cellular metabolism that drive aging are selected for in the course of evolution, and these changes cause the observed damage and dysfunction in older individuals. This is the reverse of the more widespread consensus view of aging, in which dysfunction and changes in regulation of cellular metabolism are the result of stochastic molecular damage that is either hard to repair, or gradually overwhelms repair capabilities. In this case, the damage precedes and causes harmful changes in cellular function.
Today, I'll point out a novel take on programmed aging, an open access paper in which the author proposes that the important aspect of aging is that every cell division causes a reduction in mitochondrial function - a very rate-of-living sort of a concept. I can't say that I agree with it, but it is an interesting idea to try to argue one way or another. Further, I do not agree with the author's proposition that failure to date to extend human life span is a failure of the stochastic damage models of aging. No-one has really much tried to repair the damage yet. Senolytic therapies to clear senescent cells are the first approach to aging based on damage repair to have reached the stage of earnest, widespread development efforts. They do very well in the lab, in animal models of age-related disease, but human trials have only just started. The numerous other approaches, aimed at different types of damage, have yet to reach fruition. If anything, the failures of past decades represent a failure on the part of the research and development community to engage seriously with the mechanisms of damage.
In the field of research into aging taken as a whole, there is a pretty good catalog of fundamental forms of molecular damage, and there is a pretty good catalog of age-related diseases and dysfunction. The understanding of how these two are linked is, unfortunately, very poor: knowing exactly how aging progresses would require a complete map of cellular metabolism, something that is decades away from realization at the very least. Thus it is quite easy for any given aspect of aging to be claimed and fit into either programmed aging therapies or stochastic damage theories. Cellular senescence, for example, is clearly important in aging, given that clearing these cells extends life and reverses age-related disease in animal models. Does the burden of senescent cells increase with age due to rising levels of cellular damage and consequent impairment of the immune system in its role of clearing senescent cells? Or does it rises with age because of programmed epigenetic changes that diminish resilience to the senescent state by, e.g. impairing autophagy and mitochondrial function. In areas in which complexity and lack of information makes it quite challenging to produce sound proofs, theorizing is rampant.
There is considerable variation in evolutionary models for how and why a program of detrimental change over time might be selected for. Some, like the hyperfunction theory, look a lot like the standard antagonistic pleiotropy view of why evolution doesn't tend to result in adult organisms that can last indefinitely. Biological systems evolve to do very well in early life, to optimize reproductive fitness right out of the gate, regardless of later consequences. So there are developmental programs that run wild in adult life, or systems that are incapable as constituted of running indefinitely, due to inadequate repair, limited space, or other issues. Other researchers suggest that aging is selected for directly, and invoke group selection arguments to suggest that it enhances fitness in times of environmental change, or acts to reduce the odds of ecosystem collapse due to population growth.
One of the more important advances in aging research made of late may turn out to be the discovery that repair of double strand breaks in nuclear DNA is the cause of shifts in epigenetic regulation characteristic of aging. If validated, it is a mechanism by which stochastic DNA damage, different in every cell, can produce the consistent result observed in old tissues, a detrimental change in metabolism that is much the same in all cells of a given type. That might explain the general decline in mitochondrial function, autophagy, and other processes in which changes in gene expression are the proximate cause. This should also place age-related epigenetic change firmly into the stochastic damage camp of aging, a downstream consequence of molecular damage, rather than being a program of some sort.
The Mechanism of Programed Aging: The Way to Create a Real Remedy for Senescence
Despite the breathtaking progress in all areas of science, especially in biology, and the emergence of powerful new technologies, gerontology has not made any progress in extending the maximum human lifespan. The primary reason for this stagnation is that the basal postulate of the dominant concept of aging states that the genes of longevity cannot exist, while age-related organism degradation is the result of the accumulation of stochastic errors. By now, it has been shown experimentally that genes of longevity exist and that their manipulation can influence the maximal lifespan. But, the obtained empirical data have no convincing substantiation.
It is time to conclude that further research in traditional direction is hopeless and we need to revive the initial ideas of Hippocrates and Weisman, which state that the aging process is programmed via the decline in bioenergetics. All conditions are maturated already for the realization of this way. Compared to the first half of the 20th century, genetics made enormous successes, the machinery of biological energy production has been studied substantially, and a huge amount of different fundamental knowledge has been accumulated.
Since the conception of stochastic errors has been dominant until now, gerontologists have not looked into the physicochemical essence of bioenergetics. Therefore, an age-related decline in bioenergetics is usually expressed by such inexplicit terms as "a decrease [decline] in energy production", "a defect of mitochondrial function", "mitochondrial dysfunction", "a defect in mitochondrial respiration", "a decline in mitochondrial function", or "dysregulated mitochondrial dynamics". A level of bioenergetics at the current time is usually measured by the amount of oxygen absorbed per unit of time. This is enough for resolving of some specific tasks but insufficient for understanding the mechanism of programed aging and resolving the longevity problem. To achieve the main goal, it is necessary to find out what parameter of bioenergetics is directly controlled by the genetic program, what molecular mechanism performs this program.
The ATP/ADP ratio generated by the mitochondrial bioenergetics machine predetermines the capacity of any biological system to work. It is this parameter of bioenergetics that is decreased by a genetic program to drive aging. The performance efficiency of bioenergetics depends on the ATP/ADP ratio rather than the absolute value of ATP or the number of mitochondria in cells. For example, the maximum weight that a weightlifter can lift, having a certain muscle mass, depends on the ATP/ADP ratio in his mitochondria, with the number of mitochondria in muscle cells determining how many times he can lift it. Over the years, the strength decreases, even if the muscle mass and the number of mitochondria in the muscles remain the same. The value of the ATP/ADP ratio is denoted below simply as the "bioenergetics level."
The conventional viewpoint on the mechanism of the Hayflick limit, based on the telomere shortening, is now discredited. Instead, another mechanism has been put forward. According to this proposition, there is a specific checkpoint at the boundary between the G1 and S phases in the cycle of cell division called the restriction point. All normal dividing somatic cells make a cycle suspension here; but, after a certain number of reduplication cycles, this checkpoint becomes impassable and cells enter the non-dividing state. The cyclin-dependent kinase inhibitor p27 prevents passage through this restriction point. There is a special molecular mechanism for its removal, and the efficiency of its work depends on the supply of energy. When bioenergetics levels decrease under a certain threshold, this mechanism stops inhibitor removal while cell division becomes impossible.
This leads to the conclusion that the level of cell bioenergetics, and therefore age, are strictly related to the number of duplications that have elapsed. This provides grounds for concluding that the genetic program reduces the level of cell energetics production intermittently in the process of every mitosis. Thus, the core of the mechanism of programmed aging appears to be very simple: every cell division is followed by a slight decrease in energetics generation which in turn causes some decline in viability. It has been shown that, as stem cells are divided, both in vitro and in vivo, their proliferative potential decreases and they reach the Hayflick limit, i.e., stem cells also grow old. It was concluded: "a living organism is as old as its stem cells." Thus, the bioenergetics aging clock regulates the aging process both in cell culture and in an organism.
A Look Back at 2019: Progress Towards the Treatment of Aging as a Medical Condition
It is that time again, an arbitrary midwinter point in the annual pilgrimage around the sun at which we take a look back to summarize some of the high points of the past year. As has been the case for a few years now, progress towards the implementation of rejuvenation therapies is accelerating dramatically, ever faster with each passing year. While far from everyone is convinced that near term progress in addressing human aging is plausible, it is undeniable that we are far further ahead than even a few years ago. Even the public at large is beginning to catch on. While more foresightful individuals of past generations could do little more than predict a future of rejuvenation and extended healthy lives, we are in a position to make it happen.
The State of Funding
A great deal of venture funding is arriving or preparing to arrive to support biotech startups that are working on means to treat aging. This year saw the launch of the Longevity Vision Fund, among others. I can think of three groups presently working to launch new mid-sized longevity-focused venture funds in 2020, and this is as seen from my fairly sedate perch of observation, without any great attempt to reach out and ask folk for a census. This activity will have an beneficial influence on public and private funding available for fundamental science in this part of the field. It also influences non-profit advocacy, as new organizations such as the Academy for Health and Lifespan Research are created. New governmental initiatives are also emerging, such as the Healthy Longevity Global Grand Challenge, and not just in the US: the UK government is putting out position statements on health longevity. Regulators are being petitioned by the scientific community to approve treatment of aging as a recognized goal for medicine. We should expect this trajectory to continue, though beyond the clearance of senescent cells, where development of therapies is very much a going concern, few approaches to rejuvenation are very close to making the leap from laboratory to clinical development.
There is no shortage of new companies targeting aging, many of which are (unfortunately, I think) focused on manipulation of stress responses rather than rejuvenation. BHB Therapeutics works on ketosis mechanisms. Turn.bio aims to produce a safe way to partially reprogram cells in vivo, restoring youthful function. Samsara Therapeutics works on autophagy enhancement. Rejuvenate Bio works on gene therapies to slow aging, initially in dogs. My own company, Repair Biotechnologies, still young, raised a seed round to fund our work on thymic regeneration and reversal of atherosclerosis. The Oisin Biotechnologies spinoff OncoSenX also raised a seed round this year to deploy their suicide gene therapy in cancer patients, and LIfT Biosciences raised funds to develop immune cell transplants that have been shown to do very well against cancer in animal models. Underdog Pharmaceuticals is the SENS Research Foundation spinout targeting 7-ketocholesterol (which may be important in more than just atherosclerosis). They raised a seed round this year and are well on their way. Nanotics has launched a senolytics program based on interfering in mechanisms that senescent cells used to evade immune surveillance. For more you might look at the recently created Aging Biotech Info and its curated list of companies in the longevity industry.
Speaking of funding, the SENS Research Foundation year end fundraiser is coming to a close. More than three quarters of a million was donated last year. I hope that you all did your part and contributed this year - helping this form of research is the most effective form of altruism, given the size of the potential benefits. The SENS Research Foundation remains one of the most important organizations in research aimed at treating aging. Just because senolytics to clear senescent cells are a going concern, we cannot ignore the fact that the rest of the rejuvenation research agenda is nowhere near as advanced. It still needs funding, and near all funding for many of these vital projects remains philanthropic. We fund it. We are the people who make that difference, ensuring that important research projects can advance to the point at which they attract the support of more conservative, mainstream sources of large-scale funding.
Conferences and Community
These days, I'm as often as not out and about in the world raising funding or reporting on progress for a startup biotech company, Repair Biotechnologies. I'm found at many more conferences than would otherwise be the case. Side-effects of the growth of the longevity industry over the past few years include a change in the tenor of existing scientific conferences, as well the addition of new conference series on aging that are focused as much on industry as on academia. This past year, I attended and wrote up a few notes on the following events: the SENS Research Foundation / Juvenescence gathering in San Franscisco held alongside the big JPM Healthcare conference; the first Longevity Therapeutics event, also in San Francisco; the Longevity Leaders conference in London; the vitally important Undoing Aging in Berlin; Biotech Investing in Longevity in San Francisco; the Ending Age-Related Diseases conference organized by LEAF in New York; BASEL Life, Founders Forum, LSX USA, and Giant Health in quick succession later in the year; the Alcor New York Science Symposium; and the Longevity Week events in London coordinated by Jim Mellon and his allies.
Many conference presentations and interviews with members of the growing community have been published over the past year, too many to note each and every one. The few that caught my eye:
- Interviewing Kelsey Moody of Ichor Therapeutics at the Longevity Leaders Conference
- An Interview with Sebastian Aguiar of Apollo Ventures
- David Sinclair on the Academy for Health and Lifespan Research
- Video of Investor Jim Mellon Presenting at Abundance 360 Summit 2019
- An Interview with Carolina Oliveira of OneSkin Technologies
- A Few of the Many Interviews Conducted at the Undoing Aging 2019 Conference
- An Interview with Felix Werth of the German Party for Health Research
- An Interview with Aubrey de Grey at Undoing Aging 2019
- Aubrey de Grey on the Dawn of the Era of Human Rejuvenation
- An Interview with Vittorio Sebastiano of Turn.bio
- An Interview with Jim Mellon of Juvenescence at Undoing Aging 2019
- An Interview with María Blasco on Telomeres and Telomerase
- An Interview with Morgan Levine on the Epigenetic Clock
- Jim Mellon Interviewed by Adam Ford at Undoing Aging 2019
- An Interview with Reason at Undoing Aging 2019
- An Interview with Daniel Ives of Shift Bioscience
- An Interview with Tristan Edwards of Life Biosciences
- Matthew O'Connor Presenting on Underdog Pharmaceuticals at Undoing Aging 2019
- An Interview with Aubrey de Grey at Longevity.Technology
- LEAF Interviews David Sinclair
- A Perspective on Longevity Biotech Investment from James Peyer of Kronos BioVentures
- Kelsey Moody Presenting on the LysoClear Program at Ending Age-Related Diseases 2019
- An Interview with Justin Rebo of BioAge
- An Interview with Amutha Boominathan of the SENS Research Foundation
- An Interview with Sergey Young of the Longevity Vision Fund
- A Profile of Tissue Engineering Efforts at LyGenesis
- An Interview with Brian Kennedy of the Center for Healthy Aging in Singapore
- Declan Doogan of Juvenescence Presenting at Investing in the Age of Longevity
- On Making Philanthropy in Support of Rejuvenation Research Attractive to Investors
Drug development pipelines are moving forward, though not always smoothly. There is a high failure rate in the development of medical biotechnology. Eidos Therapeutics announced Phase II results for their approach to preventing transthyretin amyloid aggregation. Gensight is presently struggling with phase III for allotopic expression of mitochondrial genes - the mechanism works, the earlier trials passed, and now reaching sufficient efficacy is proving to be a challenge. Intervene Immune published interesting results from their small thymic regeneration trial, while Libella Gene Therapeutics is launching a patient paid trial for telomase gene therapy. The resTORbio approach to inhibition of mTORC1 failed a phase III trial for immunosenescence, which may or may not cast a pall over that part of the industry. The TAME clinical trial for metformin, using a new composite endpoint as a surrogate for aging, was funded this year and will start soon. This despite the point that metformin remains terrible choice of intervention, picked because the FDA couldn't object to it on technical grounds, not because anyone thinks that it will produce meaningful results for patients. Opinions are mixed on this topic.
The first human trials of senolytic therapies to clear senescent cells reported results this year, starting with promising results for lower dose dasatinib and quercetin versus idiopathic pulmonary fibrosis. Data from an as yet incomplete trial of dasatinib and quercetin versus chronic kidney disease has confirmed that these senolytics do clear senescent cells in humans in the same way as in mice. Unity Biotechnology announced results from their first trial of senolytics for osteoarthritis of the knee, and is moving on to phase II. There are those who think that there is still a long road ahead to the clinic. A trial of fisetin by the Mayo Clinic has yet to publish results, but for those who'd like to follow along at home in advance of data, the Forever Healthy Foundation published a risk/benefit analysis covering what is known of fisetin as a senolytic.
Senescent cells accumulate with age and contribute to degenerative disease, despite their many beneficial roles earlier in life. Senolytics to selectively destroy lingering senescent cells continue to show great promise in animal models, and as a class of therapy appear about as close to a panacea as it is possible to be. New supporting evidence published over the course of 2019 offers the potential of effective treatment for a range of conditions: Alzheimer's disease, osteoporosis, osteoarthritis, rheumatoid arthritis, atherosclerosis, cardiac fibrosis and hypertrophy, periodontitis, pulmonary fibrosis, cataracts, aortic aneurysm, acute kidney injury, chronic kidney disease, heart failure, type 1 diabetes, type 2 diabetes, thrombosis, degenerative disc disease, immunosenescence due to changes in hematopoiesis, pulmonary disease resulting from smoking, age-related loss of liver function, neurodegeneration through astrocyte senescence, recovery from heart attack, and recovery from chemotherapy. The accumulation of senescent T cells is an important component of immune aging and chronic inflammation, including some of the issues observed in type 2 diabetes. Visceral fat tissue produces many of its harmful effects via the generation of more senescent cells than would otherwise be created.
Any number of compounds are under evaluation as potential senolytics, though we should always be skeptical of effect size until animal data is in hand, particularly when the compounds include those already in widespread use, as drugs, supplements, or components of diet. Compounds recently examined for senolytic effects include circumin analogs, the fibrate class of drugs used to treat raised blood lipid levels, cardiac glycosides used in treatment of aspects of heart disease, and quercetin coated nanoparticles. Other approaches also exist: exosomes from embryonic stem cells clear senescent cells, and it may be possible to interfere in the mechanisms that senescent cells use to evade the immune system. Further, designed compounds that are transformed into toxins by senescence-associated β-galactosidase, which is upregulated in senescent cells, appear a promising line of attack.
A great deal of research is ongoing into the biochemistry of cellular senescence, not least because any particular mechanism might turn out to be the basis for therapies that meaningfully turn back aging - there is a little of the element of a gold rush to the work. Senescent cells are large because they produce too much protein in expectation of cell division that doesn't occur - or possibly also because they consume neighboring cells. The ceremides found in extracellular vesicles increase senescence. Versican may link the hyperglycemic diabetic metabolism to increased vascular calcification via cellular senescence. The harmful secretions of senescent cells, the senescence-associated secretory phenotype (SASP) depend on certain aspects of the heterochromatin. The activity of L1 retrotransposons also appears relevant to the SASP. Naked mole-rat senescent cells do not exhibit the SASP, which goes a long way towards explaining how this species can exhibit robust good health even while accumulating senescent cells just like other mammals. Meanwhile, researchers are producing a comprehensive map of all of the molecules making up the SASP, many of which are conveyed via exosomes. Another group has published a database of senescence-associated genes. Acute myeloid leukemia turns out to produce senescent cells to aid its own growth. The gene ccna2 is a regulator of the senescent state. Rising levels of aneuploidy may be important in increasing numbers of senescent cells. Upregulation CBX4 or DGCR8 reduces senescence in mice. Melanocytes are the only epidermal cell type to exhibit senescence. Age-related AT1 autoimmunity may spur generation of senescent cells in vascular tissue, and consequent vascular dysfunction.
An important part of the senolytics industry, and one that has so far lagged behind, is the ability to quantify the number of senescent cells in different tissues by age, along with their pace of creation. A start on senescence burden by tissue and age was published this year for mice, accompanied by a good review on the far patchier data for humans. Are these errant cells lingering for years on end, or is turnover and clearance still happening in very old people, and just needs a helping hand? Recent work on topical rapamyin for skin aging and the speed of senescent cell clearance by age suggests that the latter model is more the case. Answering these questions robustly will require better means of quantifying senescence in patients without restoring to a biopsy. This might be achieved via fluorescent reporter genes, or, for senescence in the kidney, by suitable urinalysis. It will likely also require better and more consistent signatures of cellular senescence.
Mitochondria in Aging
Mitochondrial function is clearly important in the progression of aging. Why does it falter consistently in cells throughout the body? Proximate causes appear to involve a loss of fission, leading to worn and damaged mitochondria that are too large to be effectively cleared by mitophagy; this appears to be related to changing expression of PUM2 and MFF, but how that relates to the underlying molecular damage of aging remains a question.
A method of enhancing mitophagy has been shown to improve mitochondrial function in old humans. Other approaches to mitochondrial decline are at various stages of development, such as delivering entire mitochondria that are taken up by cells and put to work. The SENS Research Foundation team continues to work on allotopic expression of mitochondrial genes as a way to prevent certain forms of mitochondrial DNA damage from causing cells to become pathological, and crowdfunded one of the next steps in their program this year.
Efforts to increase NAD+ levels in old mitochondria are enjoying considerable support at present, though it remains to be proven rigorously that they are producing benefits in the many people who are chosen to employ the various supplements. Animal studies and human trials continue, as does the more fundamental research into the biochemistry of NAD+ in mitochondria. An NMNT inhibitor improves NAD+ salvage to increase stem cell function. Nicotinamide riboside improves intestinal stem cell function. The levels of eNAMPT may be important in the way nicotinamide mononucleotide supplementation increases NAD+. Increased NAD+ levels also slows age-related hearing loss in mice.
Nuclear DNA Damage
Random mutations can spread through a tissue when they occur in stem cells or progenitor cells. There are also epigenetic mutations to consider, persistent and aberrant changes in epigenetic markers that alter the production of proteins. Is this damage a meaningful cause of aging beyond its contribution to cancer risk, though? Most mutations happen in genes that are turned off in tissues. There was a discussion earlier this year of the evidence for this sort of clonal expansion of mutations to be involved in neurodegeneration.
The most interesting new work to emerge this year suggests that repair of certain types of DNA damage causes the epigenetic changes observed to take place with age. Since this mechanism doesn't depend on the mutation of specific genes, and the effect arises wherever the DNA damage occurs in the genome, this is viable alternative to explain how mutational damage can contribute to aging in a way that is very similar in every cell, despite the random nature of the damage, and the fact that the damage largely occurs to irrelevant portions of the genome. It also has implications for the viability of epigenetic reprogramming as an intervention. That the pathological outcomes of the DNA repair deficiency Werner syndrome were shown this year to be strongly dependent on mitochondrial dysfunction, which itself emerges from changes in gene expression mediated by epigenetics, might be taken as somewhat supportive of this new line of work.
There has been little further progress towards bringing approaches to cross-link breaking into a new generation of startup companies this year. Revel Pharmaceuticals, spinning out from the Spiegel Lab at Yale, has yet to raise seed funding to progress beyond initial setup - this is taking far too long, for reasons that have little to do with the technical details. An interesting unrelated advance relates to cross-links in the lens of the eye, which are completely different from those in other tissues in the body and thus require a different approach. A cross-link breaker for these forms of cross-link was trialed for age-related presbyopia, and the results were good.
In neurodegenerative research, the concept that failing drainage of cerebrospinal fluid from the brain is an important component of these conditions is gaining support. Cerebrospinal fluid drainage clears metabolic waste from the brain - and this clearance fails with age as the channels are disrupted by tissue dysfunction. Researchers have suggested that hypertension may contribute to the effect, along with age-related declines in lymphatic vessel function, and have provided evidence for reduced flow to correlate with cognitive decline.
Another growing theme in the study of neurodegenerative conditions is the importance of chronic inflammation. This is thought to be the mechanism by which gum disease is linked to Alzheimer's risk, for example. The neuroinflammation model of Alzheimer's disease inverts the first two steps in the amyloid cascade hypothesis: instead of amyloid aggregation causing chronic inflammation, which in turn produces tau aggregation, the chronic inflammation is the whole of the cause of the early stages of the condition, with amyloid as a side-effect. Much the same view is argued for Parkinson's disease and its protein aggregates. The infection hypothesis is a different aspect of this view, in which amyloid aggregation and chronic inflammation both arise from persistent viral infection. A variant of this hypothesis places more emphasis on the way in which infection generates senescent immune cells in the brain, promoting inflammation via that path. In any of these possibilities, dysfunction in glial cells is an important part of the inflammatory process, and depleting these cells reduces inflammation and consequent tau pathology. There is evidence in mice for herpesviruses to accelerate amyloid buildup. Whatever the order of causation, there is good evidence for amyloid and tau aggregates to synergize with one another in degrading neural function.
The evidence for CMV to generate chronic inflammation and otherwise impact immune function suggests that persistent viral infection is harmful in general, not just when it comes to the brain. The immune system and its decline is an important determinant of aging, and chronic inflammation is the proximate cause of a sizable fraction of age-related disease. Complicating matters, chronic inflammation might even contribute to thymic involution, an important cause of immune aging.
The Alzheimer's community is looking for new approaches. There is an increasing focus in the Alzheimer's research community on targeting tau rather than amyloid-β. A variety of methods are under exploration. An existing farnesyltransferase inhibitor drug was found to reverse tau aggregation in a mouse model. Approaches aimed at clearance of amyloid-β have not gone away, of course, and are still very actively developed. The use of affibodies is becoming explored, to pick one example. Clearance of protein aggregates is still a comparatively underutilized approach for other neurodegenerative conditions, however. There is still work taking place, such as small molecule discovery to interfere in α-synuclein aggregation in Parkinson's disease, or catching α-synuclein aggregation in the gut before it spreads to the brain. Researchers are also investigating the heat shock response as a way to direct greater clearance of protein aggregates, as well as the far more promising use of catabodies as pioneered by Covalent Bioscience.
The blood-brain barrier has long been thought important in neurodegeneration. Dysfunction in the barrier is an early leading indicator of larger neurodegeneration, though, confusingly, amyloid aggregation can cause blood-brain barrier leakage. This dysfunction is centered around the tight junction structures of the barrier, and it isn't just neurodegenerative conditions in which this is a factor. Many forms of damage to the brain are characterized by leakage of the blood-brain barrier. Early disruption of the barrier might be due in part to increased levels of acid sphingomyelinase. The primary contribution of blood-brain barrier dysfunction to neurodegeneration may well be that leaking barrier allows the passage of cells and molecules that drive chronic inflammation in brain tissue, such as fibrinogen.
Upregulation of Cell Maintenance
Upregulation of the various cell maintenance processes in order to modestly slow aging, particularly autophagy (a process that shows up everywhere in aging) and the ubiquitin-proteasome system, is an area of active research. Autophagy is known to decline with age for a variety of reasons, such as progressive failure to form autophagosomes. Recent evidence links this decline to aging in skin, and accumulation of senescent cells in the brain.
Strangely, there hasn't been all that much progress towards the clinic over the past decade, despite all of this ongoing activity. Restoration of mitophagy has been proposed as a potential treatment for neurodegenerative conditions. Upregulation of autophagy in general has recent evidence supporting its use in slowing the progression of sarcopenia, memory B cell decline, and atherosclerosis. Researchers have also proposed altering the behavior of the proteasome to target unwanted molecules, such as those altered by misfolding, or achieving a similar effect by binding unwanted proteins to component parts of the autophagosome, ensuring they get dragged along to the lysosome for disassembly. Targeting the GATA transcription factor can upregulate autophagy. The proteasome can be made more active by increasing production of one of its component parts, which is an interesting potential strategy that is gaining some support in the research community. Improving cellular maintenance in intestinal stem cells extends life in flies, a species in which intestinal function is particularly important in aging.
In Vivo Cell Reprogramming
A number of groups are working on in vivo cell reprogramming, applying similar strategies to that used to produce induced pluripotent stem cells, but in a living animal. Turn.bio launched this year to work on a method of partial reprogramming, and another group has demonstrated regeneration from optic nerve injury. The challenge here is cancer risk, and the gains appear at this point to be some combination of restoring more youthful mitochondrial function and epigenetic control of gene expression.
Work on parabiosis continues apace, linking the circulatory systems of an old and young animal and observing the results on each. It is a way to identify factors in young blood and tissue or old blood and tissue that can slow or accelerate aging, for all that the evidence is somewhat confusing and contradictory at this time. The two companies in the space in recent years, Ambrosia and Alkahest have produced only marginal results in human trials. Researchers have found MANF as a possible factor in young blood, associated with liver function. Factors in young blood appear to influence kidney function via upregulated autophagy. It is argued that most of the effects of parabiosis are mediated by the contents of extracellular vesicles, not individually secreted proteins. Beyond parabiosis, there are other approaches that involve introducing young tissue into old animals. Researchers have shown that transplanting young bone marrow into old mice is beneficial, resulting in extended life span.
The Gut Microbiome in Aging
Research into the role of changes in the gut microbiome in aging seems to be hitting its stride. The effect size of the loss of beneficial bacteria and gain in harmful bacteria is an open question, but studies in short-lived animals suggest it might be in the same ballpark as that of exercise. Certainly, healthier older people tend to have more youthful-appearing microbial populations, and this is true for thinner, fitter individuals as well. Changes in the microbiome are shown to contribute to inflammation and vascular dysfunction, as well as neurodegenerative conditions. Further, a number of quite concrete, actionable discoveries have been made in the past few years. The secretion of proprionate improves exercise capacity, and the microbes responsible are found in athletes. Optimizing gut microbial populations for greater butyrate production is beneficial to cognitive function. The populations responsible for providing tryptophan and indole decline precipitously in the mid 30s in humans, indicating supplementation of these metabolites or restoration of the lost microbes will be beneficial when started comparatively early in adult life, well ahead of most signs of aging.
Calorie restriction slows changes in the gut microbiome, but can these age-related changes be reversed? The answer is yes: transplantation of young microbes into old animals has produced good results in animal studies. Fecal microbiota transplantation is an established procedure in human medicine for conditions in which the gut is overtaken with pathological microbes, so perhaps it would not be a huge leap to extend it to improving the elderly gut microbiome. There are other approaches: limiting energy generation by pathological bacteria can diminish these populations; immunization against flagellin causes the immune system to more aggressively cull harmful gut microbes.
Biomarkers of Aging
The measurement of aging is an important goal. Quick, low-cost, reliable assessments that can be used shortly before and shortly after application of a potential rejuvenation therapy would greatly speed development of the field. Epigenetic clocks based on DNA methylation are the best known of present development programs aimed at producing biomarkers of aging. These clocks are multiplying rapidly, and do a fair job of predicting disease risk and mortality. Epigenetic age correlates with cancer risk, for example. The GrimAge clock was announced this year, as was a ribosomal DNA focused clock. In a related part of the field of epigenetic research, it was recently found that CpG site density in the genome correlates with species life span.
The clocks are not without their challenges. We don't know what they are actually measuring, and there is no guarantee that the results will be useful for any given therapy. Troubling results have been reported, the most recent of which include the inability of the clocks to distinguish between sedendary versus active twins, and lack of correlation between telomere length measures and epigenetic clocks.
Epigenetic measures are far from the only area of focus. Other groups are set on constructing biomarkers of aging from algorithmic combinations of simple measures such as grip strength, or from the gut microbiome. In the past year, other researchers have proposed intron retention via alternative splicing, the fundamentals of systems biology, measurement of protein levels in blood, and immune system metrics as potential foundations for a biomarker.
I don't watch cancer research in as much detail as I did in past years. There is a lot of very interesting work taking place, nonetheless, and the outlook is favorable for those of us who are expecting to tackle our own cancers two decades or more in the future - survival rates continue to improve, and the technologies presently in trials or development are considerably better than past therapeutic approaches. Much of the focus these days is on the refinement of ways to unleash the immune system, removing suppression mechanisms that are preventing it from vigorously attacking tumors. For example by interfering in CD47 signaling or the newly discovered similar role for CD24. There are also more speculative early stage approaches such as permanently increasing the number of natural killer cells to reduce cancer risk, or clearing out subsets of tumor associated macrophages that appear to be suppressing anti-tumor immune function.
That said, some more exciting work turns up at early stages, such as a potentially safe way to suppress telomerase activity. All cancers require lengthening of telomeres, via telomerase or ALT. Turning that off could be a universal cancer therapy. On the ALT side of the house, researchers have found that inhibition of FANCM activity is a potential point of intervention.
The Genetics of Longevity
All things genetic continue to attract a great deal of funding. This is an age of low-cost, high-capacity genetic tools - but given a hammer, perhaps too many things start to look like a nail. Studies of recent years have shown over and again that genetic contributions to human variance in aging are near entirely some combination of rare and inconsistent, small in effect size, and overall not all that important. Essentially, we all age in the same way, because of the same causes, and the observed variance is largely down to environment, chance, and choice. Based on this, I predict, and we can come back and look at this prediction in a few years, that the benefits produced by senolytic rejuvenation therapies will be very little affected by human genetic variation, as this form of therapy targets a mechanism in which the size of effect is significantly larger than the variance in that effect.
Efforts are underway to replace first generation cell therapies of many sorts, some of which were never even deployed to the clinic, with the delivery of extracellular vesicles harvested from those cells. This appears a very promising line of work. Development is underway aimed at skin regeneration, such as via increased collagen production, as well as osteoporosis and thymic regrowth. One can also mix and match: use exosomes to make a cell therapy more effective. Another possible approach to the replacement of cell therapies is reprogramming of cells in situ, such as to make astrocytes or glial cells become neurons in the brain, or turning supporting retinal cells into photoreceptors, heart fibroblasts into cardiomyocytes, or inner ear cells into sensory hair cells to replace losses. There is also considerable interest in rejuvenating stem cell populations in situ via signaling molecules, gene therapies (such as upregulation of GAS1 in muscle stem cells, or Nrf2 for degenerative disc disease), or other strategies.
Cell therapies are of course still very much a going concern, for all that their implementation in the clinic has proven to be challenging. There are some surprising successes in animal models, such as the use of a stem cell therapy to restore lost sense of smell in mice. Researchers are working on ways to replace lost cell populations or influence disease processes in Parkinsons's disease, atherosclerosis, corneal damage, and hearing loss, just to list a small selection of work from the past year. A large part of working towards success in this goal is to ensure that more cells survive and engraft, and that might be achieved by as simple an approach as culling less healthy cells prior to transplant. The march towards more cost-effective means of cell therapy continues, with the creation of cell lines that can be used in every patient being a priority. That reprogramming cells into induced pluripotent stem cells reverses epigenetic signatures of aging seems like a good reason to put more effort into using these cells as a basis for therapy.
In the tissue engineering space, the research and development community continues to move towards the growth of human organs in animals as a source for transplantation. Meanwhile, organoids are being generated for many tissue types; work on the kidney is being carried out by numerous research groups. Further, some organs are simple enough that simpler, artificial versions are useful - artificial lymph nodes, for example, are a popular topic. Or bioprinted corneal tissue. Arguably the biggest advances of the past year have been demonstrations of printed tissue incorporating microvasculature, either directly printing vascular channels, via a form of sacrificial embedded printing, or by providing a mix of cells that generates a vasculature in and of itself, potentially working around the limits to size on engineered tissues. Justifiably, these advances received considerable attention.
Odds and Ends
As is usually the case, a range of scientific work was published this year relating to approaches that could in principle lead to enhancement biotechnologies that would improve health and capabilities for everyone, not just sick people. There is, sadly, near zero chance that most such approaches will be developed to the point of robust function and widespread availability, given the present regulatory environment. To pick a few examples: symbiotic bacteria that increase oxygen availability in tissues; CXCL12 promotes small artery growth, providing alternative paths for the bloodstream that can reduce mortality and harm from heart attacks and similar blood vessel blockages. One of the possible exceptions to the absence of development efforts is delivery of soluable klotho, which has been picked up by Unity Biotechnology to expand their pipeline beyond senolytics.
There are of course any number of other topics I could have discussed at greater length and chose to skip over for the sake of time. Destruction and recreation of the immune system as a way to put autoimmunity into remission continues to be promising, and continues to need a better, safer approach than hematopoietic stem cell transplantation. Age-associated B cells are a good target for more selective destruction, though, as ever, it doesn't fix as many problems as we'd like it to. Being fit is good for you, and in a world without rejuvenation therapies, exercise capacity is a better predictor of mortality than chronological age. Reversal of atherosclerosis is ever an interesting topic, and earlier this year I summarized some of the past work in this part of the field in the context of nattokinase. In this context, it is fascinating that humans seem to need far less cholesterol than we actually have in our bloodstreams, even in a healthy state. Naked mole-rats have a far more effective and resilient metabolism than other mammalian species, and it is possible that improved mitochondrial antioxidants might be a part of that general superiority - though this is a species that thrives under high oxidative stress. There was a sizable debate over whether or not Jeanne Calment was actually aged 122 at death. Late life mortality is in general tough to examine because the data is of a terrible quality, which makes it difficult to debate propositions such as whether or not there is a limit to human longevity in the present environment of slowly increasing life spans. Does obesity actually accelerate aging? Quite likely yes. Declines in the density of microvasculature may be an important mediating process in aging, linking fundamental molecular damage to declining tissue function as a consequence. TDP-43 protein aggregation is a comparatively newly discovered form of proteopathy causing neurodegeneration, and researchers continue to explore the implications. Human cell division rates decrease with age, which might explain why cancer risk actually declines in very late life. Amyloid buildup in the heart correlates with the risk of atrial fibrillation, adding to data from past years showing that amyloid contributes to heart disease and cardiac mortality. Dogs are a possibly underused model for aging research; that underuse might change with the growth of the Dog Aging Project.
As usual, a number of short articles were written over the past year, though it seems I'm doing this less often than used to be the case. Time is ever fleeting.
- Request for Startups in the Rejuvenation Biotechnology Space, 2019 Edition
- Rejuvenation Therapies Will Also Have Cycles of Hope and Disillusionment
- The Cosmological Noocene
- Taking the Founders Pledge to Donate to Charity Following a Liquidity Event
- How to Start a Biotech Company in the Longevity Industry
A great deal of progress is being made in the matter of treating aging: in advocacy, in funding, in the research and development. It can never be enough, and it can never be fast enough, given the enormous cost in suffering and lost lives. The longevity industry is really only just getting started in the grand scheme of things: it looks vast to those of us who followed the slow, halting progress in aging research that was the state of things a decade or two ago. But it is still tiny compared to the rest of the medical industry, and it remains the case that there is a great deal of work yet to be done at all stages of the development process. Senolytics must reach the clinic and widespread availability, and that will involve the deployment of vast amounts of funding. At the same time, however, numerous other equally important lines of rejuvenation research are still largely stuck in the labs or in preclinial development at best. There is much left to accomplish.
Senolytic Therapies as Preventative Medicine for Glaucoma
Lingering populations of senescent cells grow with age, and cause considerable harm via their inflammatory secretions. They are a tool to promote regeneration and resistance to cancer in the short term, but like many short term systems, they become damaging when left switched on for the long term. As I noted just yesterday, even looking at only the past year of studies of senolytic therapies to selectively destroy senescent cells, there is strong evidence in animal models for their ability to prevent or reverse a score of common age-related conditions, a broad range from Alzheimer's disease and other forms of neurodegeneration to fibrosis of the heart and kidney. This is just a starting point. Senolytics have yet to be tested in earnest for many more conditions that could plausibly be reversed by the targeted removal of senescent cells; there is only so much funding, and only so many scientists.
As the study of senescent cells in the context of aging expands, with the continued influx of new funding driven by a growing interest in this part of the field, we should expect to see ever more examples such as the one I'll note today. This is yet another age-related condition with poor treatment options in which animal models are shown for the first time to benefit from the application of senolytics.
In this case the condition is glaucoma, loss of vision caused by degeneration of retinal ganglion cells and the optic nerve. In most cases - but not all - this is caused by increased pressure in the eye, driven by hypertension and degeneration of fluid channels responsible for draining the eye. The precise nature of the relationship between risk factors such as pressure and mechanisms of neural degeneration in the eye has been far from clear, unfortunately. In this context, it is a ray of hope that the research here demonstrates cellular senescence as an important mediating mechanism, showing that removal of these cells prevents half of the retinal ganglion cell death that is produced in a model of raised pressure in the eye.
Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension
Glaucoma is comprised of progressive optic neuropathies characterized by degeneration of retinal ganglion cells (RGC) and resulting changes in the optic nerve. It is a complex disease where multiple genetic and environmental factors interact. Two of the leading risk factors, increased intraocular pressure (IOP) and age, are related to the extent and rate of RGC loss. Although lowering IOP is the only approved and effective treatment for slowing worsening of vision, many treated glaucoma patients continue to experience loss of vision and some eventually become blind. Several findings suggest that age-related physiological tissue changes contribute significantly to neurodegenerative defects that cause result in the loss of vision.
Mammalian aging is a complex process where distinct molecular processes contribute to age-related tissue dysfunction. It is notable that specific molecular processes underlying RGC damage in aging eyes are poorly understood. While no single defect defines aging, several lines of evidence suggest that activation of senescence is a vital contributor. In a mouse model of glaucoma/ischemic stress, we reported the effects of p16Ink4a on RGC death. Upon increased IOP, the expression of p16Ink4a was elevated, and this led to enhanced senescence in RGCs and their death. Such changes most likely cause further RGC death and directly cause loss of vision. Of particular note, a recent bioinformatic meta-analysis of a published set of genes associated with primary open-angle glaucoma (POAG) pointed at senescence and inflammation as key factors in RGC degeneration in glaucoma.
Glaucoma remains relatively asymptomatic until it is severe, and the number of affected individuals is much higher than the number diagnosed. Numerous clinical studies have shown that lowering IOP slows the disease progression. However, RGC and optic nerve damage are not halted despite lowered IOP, and deterioration of vision progresses in most treated patients. This suggests the possibility that an independent damaging agent or process persists even after the original insult (elevated IOP) has been ameliorated.
We hypothesized that early removal of senescent RGCs that secrete senescent associated secretory proteins (SASP) could protect remaining RGCs from senescence and death induced by IOP elevation. To test this hypothesis, we used an established transgenic p16-3MR mouse model in which the systemic administration of the small molecule ganciclovir (GCV) selectively kills p16INK4a-expressing cells. We show that the early removal of p16Ink4+ cells has a strong protective effect on RGC survival and visual function. We confirm the efficiency of the method by showing the reduced level of p16INK4a expression and lower number of senescent β-galactosidase-positive cells after GCV treatment. Finally, we show that treatment of p16-3MR mice with a known senolytic drug (dasatinib) has a similar protective effect on RGCs as compared to GCV treatment in p16-3MR mice.
Better Characterizing the Clonal Expansion of Somatic Mutations in Aging Tissues
Mutational damage to nuclear DNA occurs constantly in all cells, and not all of it is successfully repaired. Setting aside recent evidence for cycles of damage and repair to cause epigenetic changes characteristic of aging, most unrepaired mutational damage has no meaningful consequence. It occurs in somatic cells that have few cell divisions left, so will not spread, and these cells will die or become senescent and be destroyed once they reach the Hayflick limit. It occurs in genes that are not active in the tissue in question, so even in long-lived somatic cells that do not replicate, such as those of the central nervous system, most mutations will be irrelevant to function.
So how might this process significantly affect tissue function and health? Firstly, mutations or combinations of mutations to a small number of important genes can make a cell cancerous, leading to unfettered replication and a tumor if not stopped by the immune system. Secondly, mutations that take place in a stem cell or progenitor cell can spread widely into tissue, and if they happen to change function in some way, that might contribute to age-related decline. There is no good evidence for the size of this effect, however. A first step on the way towards gathering that evidence is mapping the extent of somatic mutation and its clonal expansion in aged tissues, a project that is still ongoing in the research community.
Should somatic mutation turn out to be an important contributing cause of aging, what can be done about it? Targeted destruction of damaged cells might be off the table, given the size of the mutated cell population, and in any case there is the question of how to identify an enormous number of different stochastic mutations in order to trigger a suicide gene therapy or similar in only the desired cells. This is not a simple proposition. Periodic replacement of stem cell populations seems the most viable of options, as it would make the necessary gene therapy a somewhat easier prospect - it only has to be accomplished in the transplanted stem cells, rather than throughout the body. But again, identifying and fixing tens of thousands of broken genes, even in a petri dish, is certainly not a near term prospect. Indeed, viable methods of robustly replacing stem cell populations are still only in the earliest stages of development at this time. These are tools of the 2030s and 2040s, building atop a much more developed industry of gene therapy and regenerative medicine.
The somatic mutation landscape of the human body
In humans, somatic mutations play a key role in senescence and tumorigenesis. Pioneering work on somatic evolution in cancer has led to the characterization of cancer driver genes and mutation signatures; the interplay between chromatin, nuclear architecture, carcinogens, and the mutational landscape; the evolutionary forces acting on somatic mutations; and clinical implications of somatic mutations. Somatic mutations have been far less studied in healthy human tissues than in cancer. Early studies focused on blood as it is readily accessible and because of the known effects of immune-driven somatic mutation. Recently, somatic mutations have been characterized in tissues like the skin, brain, esophagus, and colon. These studies confirmed that cells harboring certain mutations expand clonally, and the number of clonal populations - as well as the total number of somatic mutations - increases with age. Additionally, recurrent positively selected mutations in specific genes (e.g., NOTCH1) were observed. However, a more comprehensive understanding of somatic mutations across the human body has been limited by the small number of tissues studied to date.
Most studies on somatic evolution in healthy tissues have sequenced DNA from biopsies to high coverage. However, the transcriptome also carries all the genomic information of a cell's transcribed genome, in addition to RNA-specific mutations or edits. RNA-seq has been used to identify germline DNA variants, and recently, single-cell (sc) RNA-seq was used to call DNA somatic mutations in the pancreas of several people. To systematically identify somatic mutations in the human body and to investigate their distribution and functional impact, we developed a method that leverages the genomic information carried by RNA to identify DNA somatic mutations while avoiding most sources of false positives. We applied it to infer somatic mutations across 7500 tissue samples from 36 non-cancerous tissues, allowing us to explore the landscape of somatic mutations throughout the human body. To our knowledge, this is the largest map to date of somatic mutations in non-cancerous tissues.
It has been proposed that somatic mutations contribute to aging and organ deterioration; consistently, we observed a positive correlation between age and mutation burden in most tissues. Interestingly, several brain regions are among the tissues exhibiting stronger age correlation, and somatic mutations have been shown to have a role in neurodegeneration. We observed largely tissue-specific behaviors and some pervasive observations shared across tissues. These results suggest that different cell types are subjected to different evolutionary paths that could be dependent on environmental or developmental differences. For example, while most samples exhibit tissue-specific mutation profiles, some others like transverse colon and the small intestine have similar profiles. Additionally, we observed that genes whose expression is associated with mutation load in several tissues are enriched in DNA repair, autophagy, immune response, cellular transport, cell adhesion, and viral processes, and while these functions have been implicated in mutagenesis in cancer, our results highlight how expression variation of these genes associates with mutational variation in healthy tissues.
Our findings paint a complex landscape of somatic mutation across the human body, highlighting their tissue-specific distributions and functional associations. The prevalence of cancer mutations and positive selection of cancer driver genes in non-diseased tissues suggests the possibility of a poised pre-cancerous state, which could also contribute to aging. Finally, our method for inferring somatic mutations from RNA-seq data may help accelerate the study of somatic evolution and its role in aging and disease.
Building a Biomarker of Aging from Frailty Measures
A biomarker of aging is a a way to measure biological age, the burden of cell and tissue damage and consequent dysfunction. A biomarker that permitted the robust, quick, and cheap assessment of biological age would greatly speed up development of rejuvenation therapies. It would allow for rapid and cost-effective tests of many interventions, and the best interventions would quickly rise to prominence. At present the rigorous assessment of ways to intervene in the aging process is slow and expensive, as there is little alternative but to run life span studies. Even in mice that is prohibitively costly in time and funds for most research and development programs.
One of the more severe consequences of this state of affairs is that it takes a long time and sizable expense to weed out the less effective approaches to treatment. That this is a problem is well recognized by the scientific community, and many varied biomarkers of aging are presently under development. Perhaps the best known are the various forms of epigenetic clock, weighted algorithmic combinations of the status of DNA methylation sites that correlate with age and mortality risk. There are other approaches, though, such as combining simple measures of decline such as grip strength or inflammatory markers in blood tests. That class of methodology is explored in today's open access paper, with the focus specifically on measures adopted by the clinical community to assess frailty.
One of the concerns with the epigenetic clock, and for similar efforts using levels of blood proteins, is that it is quite unclear as to what exactly is being measured. The relationship with age and mortality emerges from the data, and it is then up to the research community to establish mechanistic connections between specific epigenetic changes and underlying processes of aging. It is quite possible that these biomarkers do not reflect all of the mechanisms of aging, and thus any use of them to assess a specific approach to rejuvenation would have to be carefully validated in parallel with the development of that therapy. This somewhat defeats the point of the exercise. When building a biomarker based on frailty indices, as here, there is at least a greater degree of confidence that it comprehensively touches on all of the contributions to aging, and we would thus expect any viable rejuvenation therapy to make a difference to the measure of age.
Age and life expectancy clocks based on machine learning analysis of mouse frailty
Biological age is an increasingly utilized concept that aims to more accurately reflect aging in an individual than the conventional chronological age. Biological measures that accurately predict health and longevity would greatly expedite studies aimed at identifying novel genetic and pharmacological disease and aging interventions. Any useful biometric or biomarker for biological age should track with chronological age and should serve as a better predictor of remaining longevity and other age-associated outcomes than does chronological age alone, even at an age when most of a population is still alive. In addition, its measurement should be non-invasive to allow for repeated measurements without altering the health or lifespan of the animal measured.
In humans, biometrics and biomarkers that meet at least some of these requirements include physiological measurements such as grip strength or gait, measures of the immune system, telomere length, advanced glycosylation end-products, levels of cellular senescence, and DNA methylation clocks. DNA methylation clocks have been adapted for mice but unfortunately these clocks are currently expensive, time consuming, and require the extraction of blood or tissue.
Frailty index assessments in humans are strong predictors of mortality and morbidity, outperforming other measures of biological age including DNA methylation clocks. Frailty indices quantify the accumulation of up to 70 health-related deficits, including laboratory test results, symptoms, diseases, and standard measures such as activities of daily living. The number of deficits an individual shows is divided by the number of items measured to give a number between 0 and 1, in which a higher number indicates a greater degree of frailty. The frailty index has been recently reverse-translated into an assessment tool for mice which includes 31 non-invasive items across a range of systems. The mouse frailty index is strongly associated with chronological age, correlated with mortality and other age-related outcomes, and is sensitive to lifespan-altering interventions. However, the power of the mouse frailty index to model biological age or predict life expectancy for an individual animal has not yet been explored.
In this study, we tracked frailty longitudinally in a cohort of aging male mice from 21 months of age until their natural deaths and employed machine learning algorithms to build two clocks: FRIGHT (Frailty Inferred Geriatric Health Timeline) age, designed to model chronological age, and the AFRAID (Analysis of Frailty and Death) clock, which was modelled to predict life expectancy. FRIGHT age reflects apparent chronological age better than the frailty index alone, while the AFRAID clock predicts life expectancy at multiple ages. These clocks were then tested for their predicitve power on cohorts of mice treated with interventions known to extend healthspan or lifespan, enalapril and methionine restriction. They accurately predicted increased healthspan and lifespan, demonstrating that an assessment of non-invasive biometrics in interventional studies can greatly accelerate the pace of discovery.
A Discussion of Relaxin as a Possible Treatment for Heart Failure
The hormone relaxin did well in an early clinical trial as a treatment for heart failure, but failed in a larger trial. Researchers here determine that the benefits observed in animal models and patients are probably due to interactions between relaxin and Wnt signaling, a pathway important in regeneration. The actions of this pathway are very complicated and situational, as is true of most regulators of development and regeneration. Given the presently successful trajectory of Samumed, a regenerative medicine company focused on developing therapeutics based on manipulation of Wnt signaling, it is understandable that numerous other groups have attempted much the same in recent years. Manipulation of pathways central to processes such as regeneration is a road littered with failures, unfortunately, thanks to the complexity of the biochemistry.
Based on intriguing clinical and pre-clinical data, relaxin (RLX) engendered significant enthusiasm as a potential therapy for cardiopulmonary diseases. In the acute heart failure trial RELAX-AHF, RLX treatment improved patient survival by a remarkable 37% in 6 months. These exciting results led the FDA to declare RLX as a "break-through" therapy made all the more significant because the trial included patients with systolic and diastolic HF. Unfortunately, the reduced mortality benefits were not duplicated in a subsequent larger clinical trial sponsored by Novartis.
Detailed analysis of the larger trial has not been reported and the failure of RLX to significantly reduce mortality is not fully understood. A possible explanation is that the control group of patients receiving standard of care for heart failure fared considerably better than in earlier trials but another problem has been the design methodology of a 2-days treatment which has justifiably received substantial criticism. Our previous studies on the effects of RLX in experimental animals provide compelling evidence of significant beneficial effects of the hormone in cardiac physiology. We reported that RLX suppressed atrial fibrillation in aged rats by increasing conduction velocity (CV) of atrial action potentials. These effects were linked to increased expression of the voltage-gated sodium channel (Nav1.5), and a marked decrease in fibrosis, both effects confirmed here in ventricles. At the cellular level, the reversal of fibrosis required more than a week due to the slow turn-over of collagen in the extracellular matrix. Besides electrical and extracellular matrix remodeling, we reported that RLX acted as a potent anti-immune and anti-inflammatory agent in the ventricles of aged animals.
Our results show that RLX's effects in heart tissue are largely mediated by the modulation of canonical Wnt signaling which can act as a master controller of gene expression in heart and other organs. While RLX and Wnt signaling have been investigated in models of cancer, there is no work on the interactions of the RLX and Wnt pathways in adult heart and 'healthy' aging as a precursor of cardiac diseases. Wnt signaling in the heart is complex, and different Wnt ligands have distinct effects. Many details of the mechanism by which RLX modulates canonical Wnt signaling remain to be explored. Nonetheless, these findings demonstrate a close interplay between RLX and Wnt-signaling resulting in myocardial remodeling and reveal a fundamental mechanism of great therapeutic potential.
Autophagy as a Common Denominator of Age-Slowing Interventions in Animal Models
Most of the interventions shown to slow aging in short-lived laboratory species produce their effects through upregulation of autophagy, a collection of cellular maintenance processes that recycle damaged or unwanted proteins and cell structures. This is an important part of the cellular response to various stresses, from heat to lack of nutrients. Since short-lived species have quite plastic life spans when subjected to this sort of stress, particularly to calorie restriction, and since these mechanisms have many component parts that influence the whole, ways to trigger stress response pathways have tended to be the interventions discovered by screening of compound libraries.
Aging is accompanied by progressive decline of autophagy in many organisms. A reduction in autophagy during aging was demonstrated in a study that carefully examined autophagy in different tissues throughout adulthood of long-lived daf-2 and glp-1 C. elegans mutants, and showed that the intestinal inhibition of autophagy abolishes longevity only in glp-1 mutants. In mice, neuronal and glial specific deletion of either of essential autophagy genes atg5 and atg7 results in short-lived animals displaying neuronal protein accumulation and neurodegeneration. This highlights the importance of autophagy in removing damaged proteins in non-dividing neuronal tissue, and the potential of therapeutic autophagy enhancement in neurodegenerative disease.
Evidence for the role of autophagy in aging was first shown in daf-2 long-lived worms, where RNAi-mediated downregulation of the autophagy gene bec-1 completely abrogated their pronounced longevity. Since this discovery, dependence on autophagy enhancement has been demonstrated in nearly all longevity-promoting interventions. For instance, lifespan extension by dietary restriction, mTOR inhibition, AMPK up-regulation, mitochondrial mutations, and the above mentioned germline glp-1 mutation, all require functional autophagy for lifespan extension. In all these long-lived mutants, lessening autophagy by RNAi returns lifespan toward wild type levels. However, controls treated with similar autophagy-reducing RNAi interventions do not display altered longevity, suggesting that the residual autophagy levels are sufficient to maintain normal lifespan. It is worth noting that the nutrient-sensing pathways implicated in longevity have pleiotropic effects on metabolism, and often, under conditions when autophagy is up-regulated, this also impacts on other anti-aging processes such translation. It is thus challenging to fully evaluate exact contributions of different down-stream effectors on overall longevity.
Manipulations that increase autophagy directly are valuable but sparse, and complicated by the fact that that numerous autophagy genes are involved in different stages of this multistep process. Moreover, overexpression of only one autophagy gene does not necessarily trigger autophagy. Nevertheless, there are some very valuable exceptions that directly show how important this process is in aging. For instance, overexpression of Atg8a in neurons, as well as Atg1 overexpression in neuronal tissue or muscle, extends lifespan in Drosophila. In addition, mammalian lifespan was extended by an ubiquitous increase of Atg5 in mice, and was accompanied by improved motor function. Further studies of autophagy manipulation in different tissues will help to elucidate further tissue-specific effects and the impact of these on organismal aging. In particular, combining longevity experiments with healthspan parameters, such as motor function, cardiovascular deterioration, neuronal loss, and insulin sensitivity, will facilitate the discovery of pharmacological targets for disease prevention and treatment.
A Fourfold Greater Risk of Cardiovascular Mortality in Women with Poor Fitness
The research results here are a reminder that exercise has a meaningful effect on long-term health. Agreeing with the outcomes from many other epidemiological studies, the data here shows a significantly higher risk of mortality due to cardiovascular disease for individuals possessed of a lesser capacity for exercise. Human studies largely only show correlations between exercise and age-related disease risk, leaving open the question of the direction of causation, but the equivalent animal studies quite comprehensively demonstrate that exercise lowers risk of age-related disease. Regular exercise and maintenance of physical fitness are good for you.
Exercise is good for health and longevity, but information on women is scarce. Women generally live longer than men, so dedicated studies are needed. This study examined exercise capacity and heart function during exercise in women and their links with survival. The study included 4,714 adult women referred for treadmill exercise echocardiography because of known or suspected coronary artery disease. Most study participants were middle aged or older women: the average age was 64 and 80% were between 50 and 75.
Participants walked or ran on a treadmill, gradually increasing the intensity, and continuing until exhaustion. Images of the heart were generated during the test. Fitness was defined as a maximal workload of 10 metabolic equivalents (METs), which is equal to walking fast up four flights of stairs or very fast up three flights, without stopping. Women who achieved 10 METs or more (good exercise capacity) were compared to those achieving less than 10 METs (poor exercise capacity).
During a median follow-up of 4.6 years there were 345 cardiovascular deaths, 164 cancer deaths, and 203 deaths from other causes. After adjusting for factors that could influence the relationship, METs were significantly associated with lower risk of death from cardiovascular disease, cancer, and other causes. The annual rate of death from cardiovascular disease was nearly four times higher in women with poor, compared to good, exercise capacity (2.2% versus 0.6%). Annual cancer deaths were doubled in patients with poor, compared to good, exercise capacity (0.9% versus 0.4%). The annual rate of death from other causes was more than four times higher in those with poor, compared to good, exercise capacity (1.4% vs. 0.3%).
Smooth Muscle Cells in Age-Related Vascular Degeneration and Calcification
Vascular smooth muscle cells are impacted considerably by aging, contributing to detrimental age-related remodeling of blood vessel walls in a number of ways. This includes the structural changes that accompany hypertension and atherosclerosis, as well as arterial stiffness and calcification. Insofar as calcification goes, existing evidence supports a role for the inflammatory signaling of senescent cells in driving vascular cells to behave as though they are in bone tissue, depositing calcium. The overall dysfunction of vascular smooth muscle cells is quite complex, however, and probably involves loss of mitochondrial function and other forms of damage beyond that of an inflammatory environment.
Vascular smooth muscle cells (VSMCs) are connected to a network of elastin and collagen fibers. The capacity of the vessel wall to elastically distend is important to accommodate the volume ejected with each heartbeat and to limit peripheral pressure pulsations. The spatial arrangement of VSMCs may influence the mechanical load on the extracellular matrix (ECM) components and, therefore, modulate vessel diameter and stiffness. Chronic exposure to high blood pressure increases tensile stress to which VSMCs respond by proliferation, resulting in hyperplasia and thickening of the vascular wall. Concomitant activity of matrix metallopeptidases facilitates the structural breakdown of elastin ECM, and VSMCs produce collagen ECM, attempting to preserve stiffness homeostasis. High blood pressure thus aggravates age-related stiffening of arteries. Additional ECM disturbances, such as the presence of calcium crystals, have a further impact on the stiffening of the medial layer.
During aging, it is generally accepted that the number of cells in the vasculature decreases, although the causes of this finding remain to be established. It has been hypothesized that VSMCs become senescent and that cell division rates decrease. The recent literature ignores vessel wall cellularity and often refers to cellular processes, such as apoptosis, inflammation, calcification, and epigenetic effects, all playing a part in vessel wall aging. Additionally, with aging, collagen content in major arterial vasculature increases, whereas elastin content decreases and the number of VSMCs declines. As a consequence, remaining VSMCs are embedded in a collagen-enriched ECM with fewer cellular focal adhesions.
Within arterial vessels, differences exist in the content of elastin to VSMC ratios. Large arteries close to the heart contain more elastin and are therefore called "elastic" arteries. It is particularly elastic arteries that stiffen with age. Large artery stiffening results in decreased arterial compliance, especially in those aged over 60 years. Peripheral vessels contain more VSMCs relative to elastin and are termed "muscular" arteries. In muscular arteries, the relative elastin content increases with age, most likely caused by the decline in the number of VSMCs and decreased collagen content. It should be noted that the absolute amount of ECM proteins in the vasculature decreases with age, but that fat and extracellular material, such as calcium crystals, increase. Taken together, the number of VSMCs within the vasculature strongly correlates with vascular stiffening and the arterial remodeling processes.
Intermittent Fasting is Beneficial in Humans
Evidence from the scientific community shows intermittent fasting to be beneficial in numerous species, including our own. The materials here discuss what I would call time restricted feeding rather than intermittent fasting. Restricting the hours that one eats during the day, but still otherwise eating ad libitum every day, can arguably be thought of as a mild form of intermittent fasting that doesn't rise to the level of, say, alternate day fasting or a quarterly five day implementation of the fasting mimicking diet. Nonetheless, there are benefits. It remains to be robustly determined in humans as to whether the benefits resulting from these milder forms of intermittent fasting are largely derived from a reduction in overall calories consumed or from undergoing periods of low calorie intake. Both have been shown to produce benefits in mice and rats, independently of one another.
Intermittent fasting diets fall generally into two categories: daily time-restricted feeding, which narrows eating times to 6-8 hours per day, and so-called 5:2 intermittent fasting, in which people limit themselves to one moderate-sized meal two days each week. An array of animal and some human studies have shown that alternating between times of fasting and eating supports cellular health, probably by triggering an age-old adaptation to periods of food scarcity called metabolic switching. Such a switch occurs when cells use up their stores of rapidly accessible, sugar-based fuel, and begin converting fat into energy in a slower metabolic process.
Studies have shown that this switch improves blood sugar regulation, increases resistance to stress, and suppresses inflammation for various periods of time. Because most Americans eat three meals plus snacks each day, they do not experience the switch, or the suggested benefits. Studies in both animals and people found intermittent fasting also decreased blood pressure, blood lipid levels, and resting heart rates. Evidence is also mounting that intermittent fasting can modify risk factors associated with obesity and diabetes. Two studies of 100 overweight women showed that those on the 5:2 intermittent fasting diet lost the same amount of weight as women who restricted calories, but did better on measures of insulin sensitivity and reduced belly fat than those in the calorie-reduction group.
More recently, preliminary studies suggest that intermittent fasting could benefit brain health too. A clinical trial found that 220 healthy, nonobese adults who maintained a calorie restricted diet for two years showed signs of improved memory in a battery of cognitive tests. While far more research needs to be done to prove any effects of intermittent fasting on learning and memory, if that proof is found, the fasting - or a pharmaceutical equivalent that mimics it - may offer interventions that can stave off neurodegeneration and dementia.
Controlling Hypertension Reduces Dementia Risk, but Only if Done Early
The connection between raised blood pressure and dementia is well established. Controlling hypertension via the usual combination of lifestyle choice and medications slows cognitive decline, and any number of epidemiological studies show that dementia patients are more likely to have a history of hypertension. The data noted in this review is interesting for making the point that the pressure damage to the brain and its vasculature that results from high blood pressure occurs over the course of late life, and thus reducing blood pressure has little to no effect on patients already exhibiting dementia. This is one of many areas in aging in which prevention is key, and it is well worth considering that hypertension contributes to overall mortality, not just to incidence of dementia.
Mid-life hypertension is reported to be a factor inducing dementia. Mid-life is typically defined as 45-64 years old. In this manuscript, mid-life hypertension means hypertension in individuals approximately 50 years old, and late-life hypertension means hypertension in those approximately more than 70 years old. The Atherosclerosis Risk in Communities (ARIC) cohort showed that high blood pressure in mid-life (around 48-67 years old) induces poorer cognitive function or dementia 20 years later. Moreover, the Honolulu Heart Program or Honolulu Asia Aging Study demonstrated that subjects less than 50 year old, even those with prehypertension, had an increased risk for dementia only in the untreated group.
Interestingly, subjects receiving antihypertensive medication showed no increased risk for dementia, even in those with systolic blood pressure of more than 140 mmHg, indicating that early intervention in hypertension is one approach to prevent late-life dementia. So, what is the target level of blood pressure in mid-life to prevent dementia? It was reported that systolic blood pressure elevation at age 50 years is associated with increased risk of dementia. Moreover, a systolic blood pressure level of 130 mmHg or lower has been shown to significantly prevent dementia at age 50. However, blood pressure elevation at 60 or 70 years old is not a significant risk, even in those with severe high blood pressure.
On the other hand, intervention for high blood pressure in the very elderly did not significantly reduce the incidence of dementia in the Hypertension In the Very Elderly Trial-COGnitive function assessment (HYVET-COG) trial. Moreover, the HYVET cohort study demonstrated that orthostatic hypotension indicates an increased risk of dementia and cognitive decline. Thus, intensive blood pressure treatment to prevent dementia is not recommended in "very elderly people" because blood pressure lowering fails to maintain cerebral blood flow because of dysfunction of cerebral autoregulation. Therefore, the younger the age at which blood pressure is managed at an appropriate level the better in order to prevent cognitive decline.
Impairment of the Ubiquitin Proteasome Pathway in Aging and Neurodegeneration
The ubiquitin-proteasome system acts to degrade damaged and unwanted proteins, breaking them down to constituent parts that can be recycled. Ubiquitin is used to tag proteins designated for recycling, and these are drawn into the proteasome structure to be dismantled. There is some evidence for the activity of the proteasome to decline with age, but it isn't as clear-cut as the evidence for autophagy to falter. To the degree that proteasomal activity does decline, this may be a matter of reduced expression of important component parts of the proteasome, given that increasing expression of some component proteins can improve proteasomal function, or something more complex, such as impairment of the ability of proteasomes to move around the cell. These are proximate causes, and, as is often the case, it is very unclear as to how they relate to the underlying damage that causes aging.
Ubiquitin has long been known to be associated with pathologies of the brain, including that of Alzheimer's disease (AD). Our understanding of the link between ubiquitin-mediated proteolysis and neurodegenerative diseases such as AD, however, has only begun to improve with the elucidation of the mechanistic details of protein degradation. Although proteolysis by the ubiquitin-proteasome pathway (UPP) was originally assumed to operate only on abnormal proteins, research over many years has shown physiological roles for the UPP in various cells, including neurons. Several cellular functions are altered with aging. It is reasonable to hypothesize that ubiquitin-proteasome-mediated proteolysis is also impaired with aging. Investigations, however, have not yielded consistent results.
It is generally accepted that two main types of pathological phenomena occur in the AD brain. One is the accumulation of amyloid β (Aβ), the clumps of which lead to the development of plaques. The second is the accumulation of phosphorylated microtubule-associated protein tau, which ultimately forms tangles. The UPP is linked to both of these pathways of AD pathogenesis. In AD, ubiquitinated proteins accumulate, and it is believed that the proteolytic system in neurons is overwhelmed by aggregating proteins. Based on this logic, investigations were made of the proteasome in both postmortem human AD brains and in the brains of AD model mice. Studies found that proteasome activation by rolipram - a phosphodiesterase 4 (PDE4) inhibitor - decreased tau levels and improved cognition.
Improving the function of UPP components should, in principle, ameliorate some of the symptoms of AD. Because synaptic dysfunction and cognitive impairment are seen early in AD and the UPP has a role in synaptic plasticity and memory, it might be possible to manipulate the UPP to rescue some deficits. Based on the research thus far, there is no clear-cut relationship between aging and impairment of the proteasome function. When individual molecules are studied, however, a clearer picture emerges. In investigating the connections between the UPP and AD, many studies have focused on transgenic mouse models of AD based on the familial form of the human disease. These models were mainly based on the "Aβ hypothesis" of AD. Because the link of the UPP to AD is not just through Aβ, it would be worth investigating how the UPP relates to other factors contributing to AD such as insulin resistance and inflammation in the brain.
Disruption of Mitochondrial Dynamics in Cardiovascular Disease
Mitochondria are the power plants of the cell, a herd of replicating bacteria-like organelles that contain their own small genomes. They are responsible for packaging the chemical energy store molecules used to power cell processes. Mitochondria constantly undergo fusion and fission, and otherwise promiscuously pass around their component parts. The population in each cell is gardened by the quality control mechanism of mitophagy that works to remove damaged mitochondria. There is good evidence to suggest that, with aging, changes in gene expression cause a growing imbalance between fission and fusion, leading to large mitochondria that are resistant to mitophagy even when dysfunctional. This occurs in all cells, in comparison to another mechanism by which a comparatively few cells suffer mitochondrial DNA damage that causes them to become very dysfunctional and churn out oxidative molecules that disrupt tissue function throughout the body. Loss of energy production has a major impact in all tissues, but particularly in the energy-hungry tissues of muscle and brain.
Mitochondria are highly dynamic and constantly undergo morphological changes between fission (division) and fusion in response to various metabolic and environmental cues. A fusion process assists to homogenize the contents of damaged mitochondria resulting in mitochondrial elongation. Fission, on the other hand, leads to mitochondrial fragmentation and promotes clearance of damaged mitochondria through a form of selective autophagy - mitophagy. Excessive or untimely fission or fusion may be detrimental to mitochondrial quality and mitochondrial homeostasis.
Defective segments of mitochondria are segregated from the rest of the mitochondrial network through fission for elimination by mitophagy. Fragmented mitochondria and decreased baseline of mitophagy have been noted in aging hearts. Several proteins involved in mitochondrial turnover such as PINK1 and PGC-1α tend to decrease in old animals. These data indicated a decline in the function and regulation of mitophagy during aging. Recent studies suggested that aging-related mitochondrial DNA mutations may disrupt the receptor- (NIX and FUNDC1) mediated mitophagy in the differentiation process in adult cardiac progenitor cells (CPCs), which resulted in sustained fission and less functional fragmented mitochondria. Therefore, some activators of mitophagy have been used in aging models and showed some beneficial effects. For instance, urolithin A has been widely reported to extend lifespan in C. elegans and improve physical exercise capacity in rodents through upregulating mitophagy.
However, why and how mitophagy declines during aging have not been well defined. Several hypotheses were speculated thus far. For example, it was reported S-nitrosoglutathione reductase (GSNOR/ADH5), a protein denitrosylase that regulates S-nitrosylation, was downregulated with aging in mice and humans. Accumulation of S-nitrosylation severely impaired mitophagy, rather than autophagy, leading to hyperactivated mitochondrial fission.
In essence, mitophagy is considered a self-defense and garbage removal process that maintains mitochondrial homeostasis and cellular health, in the face of pathological stimuli. Dozens of species have depicted a unique protective role of mitophagy in aging and cardiovascular diseases, an effect consistent with suppressed mitophagy in multiple pathways. The baseline of mitophagy in different cardiac diseases may help understand the complex effects of mitophagy. The presence of a switch from AMPKα2 to AMPKα1 in failing hearts has been well documented, leading to a decrease of AMPKα2-mediated mitophagy and development of heart failure. In another independent study, upregulated CK2α following acute cardiac ischemia-reperfusion injury was found to suppress FUNDC1-mediated mitophagy, leading to infarct area expansion and cardiac dysfunction. Furthermore, ischemia activated FUNDC1-mediated mitophagy while reperfusion suppressed mitophagy possibly through activating Ripk3. Not surprisingly, interventions that restored mitophagy to normal levels, but not above normal levels, in these conditions should help to maintain mitochondrial homeostasis and cellular function.
Physical Activity Correlates with Reduced Mortality
This accelerometer study retells a familiar story, in that more active individuals have a lower rate of mortality in later life. In human studies it is challenging to move beyond simple correlation between these two pieces of data - is it that more robust people who were going to live longer anyway have a greater tendency to exercise, or is it that exercise produces benefits to health? The animal studies are quite definitive, however, in showing that exercise improves long term health and reduces incidence of age-related disease, even if it doesn't tend to increase overall life span in the same robust way that calorie restriction does.
Physical activity (PA) is an important determinant of health worldwide. It is estimated that inactivity causes 9% of premature mortality, approximately 5.3 million deaths a year. Although noncommunicable diseases (NCDs) that can be prevented by PA are associated with a higher proportion of deaths in high-income countries, high mortality rates due to these diseases are also observed in middle- or low-income countries, along with important mortality from communicable diseases.
Several studies have described an existing relationship between PA in older adults and the risk of all-causes mortality. These studies differ concerning PA assessment, length of follow-up, ethnicity, age at baseline, stratification variables, and other aspects, making comparison difficult. Newer literature with objectively measured PA using accelerometers suggests that increasing light physical activity (LPA) may also be important for reducing mortality in adults and older adults. This study aims to overcome some of the previous gaps in the scientific literature by evaluating the relationship between PA, measured by accelerometry and questionnaire, and risk of all-cause mortality in community-dwelling older adults from a Southern Brazilian city.
A representative sample of older adults (≥60 y) were enrolled in 2014. From the 1451 participants interviewed in 2014, 145 died (10%) after a follow-up of an average 2.6 years. Men and women in the highest tertile of overall PA had on average a 77% and 92% lower risk of mortality than their less active counterparts. The highest tertile of LPA was also related to a lower risk of mortality in individuals of both sexes (74% and 91% lower risk among men and women, respectively). Moderate to vigorous physical activity (MVPA) statistically reduced the risk of mortality only among women. Self-reported leisure-time PA was statistically associated with a lower risk of mortality only among men.
More Aggressive Blood Pressure Control Reduces the Structural Damage Done to the Brain
Hypertension, raised blood pressure, is very damaging to tissues and organ function throughout the body. It significantly increases the pace at which capillaries rupture, leading to small areas of cell death. The loss of function adds up, particularly in the brain, where this damage shows up as white matter lesions in imaging. The study here illustrates the damage done, and reinforces the message that control of blood pressure is very important for long term health. It has already been shown to reduce mortality, and the work here gives some insight into the mechanisms by which this reduction occurs.
It's been estimated that approximately two-thirds of people over the age of 75 may have damaged small blood vessels in the brain which are visible as bright white lesions on brain imaging. Prior research evidence has linked increased amounts of these white matter lesions in the brain with cognitive decline, limited mobility such as a slower walking speed, increased incidence of falls, and even increased stroke risk.
A clinical trial, followed 199 hypertension patients 75 years of age and older for 3 years. Throughout that time, researchers tracked the potential benefits of using an intensive anti-hypertensive medication treatment regimen to garner a 24-hour systolic blood pressure target of less than 130 mmHg compared to standard control (approximately 145 mmHg). As part of the INFINITY (Intensive Versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline In the Elderly) study, researchers assessed the older adults' mobility, cognitive function, their brain's white matter progression with magnetic resonance imaging (MRI), and tracked the occurrence of any adverse events.
While the researchers did not identify any significant differences in cognitive outcomes or walking speed between the two study groups, they did observe a significant reduction in the accumulation of brain white matter disease in those receiving the intensive treatment for blood pressure control. In fact, after three years, the accrual of white matter lesions in the brain were reduced by up to 40% in the those patients receiving the intensive blood pressure therapy compared to those who were on standard therapy. Further, study participants on the intensive therapy had a lower rate of cardiovascular events including heart attack, stroke, and hospitalization from heart failure than those on standard therapy.