With the development of rejuvenation therapies underway, and accelerating, somewhere ahead lies a dividing line. Some people will be the last to age to death, too comprehensively damaged for the technologies of the time to recover. Everyone else will live indefinitely in youth and health, protected from aging by periodic repair of the underlying cell and tissue damage that causes dysfunction and disease. Where is that dividing line? No one can say in certainty. I look at the children of today, with long lives ahead of them, and find it hard to believe that in a hundred years the problem won't be solved well in time for them to live for as long as they choose. Equally, people in middle age today will certainly benefit greatly from the advent of first generation rejuvenation technologies, such as senolytics, each narrowly focused on one mechanism of aging. Yet I'm skeptical that matters will progress rapidly enough to rescue them. So somewhere between those two points are the people on the very edge; the last mortals.

In a sense this isn't terribly profound at all. It is the same story for every as yet uncontrolled medical condition, where the medical research community is working towards effective treatments that will arrive at some uncertain future date. There will be those who are the last to die, just as the therapies that save everyone else are rolling out. It is only the magnitude that is greater in the case of aging - a hundred or a thousand times greater. Does the fact that it affects everyone mean that there will be public disorder, disputes between the first immortals and the last mortals, where only private, personal existential crises exist today? I think claims of societal unrest as a result of the realization that your children will live indefinitely, while you yourself will not, are likely overwrought.

The Last Mortals

Ever-growing lifespans are the result of regular advances in medical science. In 1900 the three leading causes of death in the United States were pneumonia/influenza, tuberculosis, and diarrhoea. Only a century and a bit on, many of the major acute illnesses are tractable. Every month brings striking new medical advances. Increasingly, medical research is shifting from acute conditions such as influenza towards chronic conditions including diabetes and Alzheimer's. Ageing is the ultimate chronic condition, and there seems to be no reason, in principle at least, that would prevent us from discovering a means of halting or reversing ageing itself.

What if that all happens sooner rather than later? But what if it's not soon enough? Imagine that, after a few more breakthroughs, a scientific consensus emerges that we will have conquered illness and ageing by the year 2119; anyone alive in 2119 is likely to live for centuries, even millennia. You and I are very unlikely to make it to 2119. But we are likely to make it relatively close to that date - in fact, relative to the span of human history, we've already made it very close right now. Think that through, carefully. What would it mean to realize that you very nearly got to live forever, but didn't? What would it mean if, in our looming senescence, we were increasingly forced to share social space with young people whose anticipated allotment of time massively dwarfs our own? We would then be the last mortals.

To be precise, the kind of immortality I have in mind can be called biological immortality. A biologically immortal organism does not die from illness or ageing - though they may still die in a plane crash. If humans acquired biological immortality, our expected lifespans would jump to enormous lengths. Almost everyone would still eventually die; statistics dictate that if you fly on planes every few weeks for eternity, eventually one will crash. This point allows us to sidestep one of the perennial questions about immortality: is endless life something we'd really want? What is distinctive for biological immortals is that death becomes only a possibility, an option, not an inevitability on a fixed timetable. This sort of immortality, I would think, is definitely not a curse. To have the option of living healthily a very long time, possibly for as long as one could want (but no longer), seems like an unmitigated blessing.

Until now, the wish for immortality was mere fantasy. No one has ever lived beyond 122 years, and no one has reasonably expected to do so. But what happens once the scientists tell us that we're drawing near, that biological immortality will be ready in a generation or two - then what? Seneca told us to meet death cheerfully, because death is "demanded of us by circumstances" and cannot be controlled. Death's inevitability is what makes it unreasonable to trouble oneself. Yet, as I've been arguing, soon death may cease to be inevitable. It may become an option rather than a giver of orders. And, as the fantasy of immortality becomes a reasonable desire, this will generate not only new sorts of failed desires, but also new ways to become profoundly envious.

Here, one of the leading researchers working on the biochemistry of senescent cells - and their relevance to aging - considers the state of development of senolytic therapies. These are treatments, largely small molecule drugs at this stage, but also including suicide gene therapies, immunotherapies, and more, that are capable of selectively destroying some fraction of the senescent cells present in old tissues. There is tremendous enthusiasm in the scientific and development communities for the potential to create significant degrees of rejuvenation via this approach. The results in mice are far and away more impressive and reliable than anything else that has yet been tried in the matter of aging and age-related disease. Simple one time treatments with senolytics lead to significant extension of life span and reversal of aspects of age-related disease. Leading researchers, of course, have to be far more muted when writing for scientific journals, so the tone here is more cautious than enthused.

Healthy aging is limited by a lack of natural selection, which favors genetic programs that confer fitness early in life to maximize reproductive output. There is no selection for whether these alterations have detrimental effects later in life. One such program is cellular senescence, whereby cells become unable to divide. Cellular senescence enhances reproductive success by blocking cancer cell proliferation, but it decreases the health of the old by littering tissues with dysfunctional senescent cells (SNCs). In mice, the selective elimination of SNCs (senolysis) extends median life span and prevents or attenuates age-associated diseases. This has inspired the development of targeted senolytic drugs to eliminate the SNCs that drive age-associated disease in humans.

SNCs produce a bioactive "secretome," referred to as the senescence-associated secretory phenotype (SASP). This can disrupt normal tissue architecture and function through diverse mechanisms, including recruitment of inflammatory immune cells, remodeling of the extracellular matrix, induction of fibrosis, and inhibition of stem cell function. Paradoxically, although cellular senescence has evolved as a tumor protective program, the SASP can include factors that stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting the development of late-life cancers. Indeed, elimination of SNCs with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.

Given that our knowledge of SNCs in vivo is limited, how should researchers identify senolytic drug targets? One strategy is to identify vulnerabilities shared by cancer cells and SNCs and then use tailored variants of anticancer agents to target such vulnerabilities to selectively eliminate SNCs. Although cancer therapeutics that interfere with cell division are unsuitable as senolytic drugs, agents that block the pathways that cancer cells rely on for survival might be worth pursuing as senolytics. For example, resistance to apoptosis (a form of programmed cell death) is a feature shared by cancer cells and SNCs. Proof-of-principle evidence for the effectiveness of this strategy comes from targeting the BCL-2 protein family members: BCL-2, BCL-XL, and BCL-W. These antiapoptotic proteins are frequently overexpressed in both cancer cells and SNCs. Two targeted cancer therapeutic agents, ABT-263 and ABT-737, have been shown to selectively eliminate SNCs in mice by blocking the interactions of BCL-2, BCL-XL, and BCL-W.

Senolytic drugs that inhibit targets originally discovered in oncology could yield promising first-generation drugs to treat humans. However, this strategy may not accomplish the long-term goal of developing ideal senolytics that selectively, safely, and effectively eliminate SNCs upon systemic administration. Efforts to identify such "next-generation" senolytics could nonetheless benefit from general principles that have been used in anticancer drug discovery. For instance, it will be important to focus drug development on age-associated degenerative diseases in which SNCs are clear drivers of pathophysiology and in which senolysis could be disease modifying (e.g., osteoarthritis and atherosclerosis).

As knowledge of the fundamental biology and vulnerabilities of SNCs expands, the rational design of targeted senolytics is expected to yield therapies to eliminate SNCs that drive degeneration and disease. This positive outlook is based on successes in oncology and because the main limitation of cancer therapies - the clonal expansion of drug-resistant cells - does not apply to SNCs. Additional confidence comes from the recent progress in bringing senolytic agents into clinical trials. The first clinical trial is testing UBX0101 for the treatment of osteoarthritis of the knee. Success in these first clinical studies is the next critical milestone on the road to the development of treatments that can extend healthy longevity in people.

Link: https://doi.org/10.1126/science.aaw1299

The authors of the open access paper here have an intriguing view of the way in which regenerative processes run awry with age, and thus contribute to the aging process. As is the case for many single mechanism proposals regarding aging, I think that the viewpoint is useful, but the mechanism in question is probably not as important to aging as proposed here - it is one of many issues. Nonetheless, this is an interesting example of the way in which it is hard to pin down the ordering of specific mechanisms in aging; it is quite possible to argue for A to cause B or B to cause A and present a good case for either. Here, for example, dysregulated regeneration is thought to be a cause of senescent cell accumulation, whereas it is equally possible to argue that the chronic inflammatory signaling produced by senescent cells disrupts the usual short-lived cycle of inflammation that is necessary to coordinate various cell populations necessary to the regenerative process.

The rate of biological aging varies cyclically and episodically in response to changing environmental conditions and the developmentally-controlled biological systems that sense and respond to those changes. Mitochondria and metabolism are fundamental regulators, and the cell is the fundamental unit of aging. However, aging occurs at all anatomical levels. At levels above the cell, aging in different tissues is qualitatively, quantitatively, and chronologically distinct. For example, the heart can age faster and differently than the kidney and vice versa. Two multicellular features of aging that are universal are: (1) a decrease in physiologic reserve capacity, and (2) a decline in the functional communication between cells and organ systems, leading to death.

Decreases in reserve capacity and communication impose kinetic limits on the rate of healing after new injuries, resulting in dyssynchronous and incomplete healing. Exercise mitigates against these losses, but recovery times continue to increase with age. Reinjury before complete healing results in the stacking of incomplete cycles of healing. Developmentally delayed and arrested cells accumulate in the three stages of the cell danger response (CDR1, 2, and 3) that make up the healing cycle. Cells stuck in the CDR create physical and metabolic separation - buffer zones of reduced communication - between previously adjoining, synergistic, and metabolically interdependent cells. Mis-repairs and senescent cells accumulate, and repeated iterations of incomplete cycles of healing lead to progressively dysfunctional cellular mosaics in aging tissues.

Metabolic cross-talk between mitochondria and the nucleus, and between neighboring and distant cells via signaling molecules called metabokines regulates the completeness of healing. Purinergic signaling and sphingolipids play key roles in this process. When viewed against the backdrop of the molecular features of the healing cycle, the incomplete healing model provides a new framework for understanding the hallmarks of aging and generates a number of testable hypotheses for new treatments.

Link: https://doi.org/10.3390/biology8020027

The lengthy and somewhat overwrought article I'll point out today is a good example of the way in which journalists fail when writing on the topic of the growing biotechnology industry that is making the first steps towards the medical control of aging. They talk to just a few people, and thus have a very narrow (generously) or absolutely incorrect (more accurately) view of what might be happening, the prospects for the future, and the shape of the field as a whole. In this case the few people are the folk at AgeLab at MIT, and George Church, with a focus on the veterinary deployment of gene therapies by Rejuvenate Bio, and a fairly traditional Alzheimer's researcher.

To speak directly, and without meaning to be cruel about it, AgeLab should not exist. It is an entity focused on coping with the realities of aging, making recommendations on small ways that older people might do a little better under the burden of aging. This is a waste of funding in a world in which there is even the slightest possibility of treating aging as a medical condition, and the present state of senolytics, among many other signs, shows that there is far more than a slight possibility of that outcome. Unfortunately AgeLab is far from the only organization set up on the premise that aging cannot be changed, and that the only thing to be done is cope. Holding it up in any discussion of where things might be going in the future is just silly. As rejuvenation works, the AgeLabs of the world will vanish, and rightfully so.

The genetic approach to aging, of using gene therapies of various sorts to adjust the operation of metabolism in late life is espoused by George Church and others. This seems to me just an incremental advance over small molecule calorie restriction mimetic or other stress response upregulation efforts. Gene therapy can be more precise, with fewer off-target effects, and a more flexible, direct development program. But at the end of the day this is still largely a case of altering metabolism to better resist aging rather than addressing the underlying causes of aging. This tweaking of metabolic processes simply cannot produce sizable benefits, as the underlying damage still exists, and the gene therapy can only tweak one set of mechanisms related to that damage, leaving all the others to fester. It will certainly look at lot better than the medicines of yesterday, which failed to even achieve this much, but why aim low? This type of approach to aging is the majority of the field still, but it is not the future of therapies for aging. The effect sizes won't be large enough and reliable enough in comparison to those of clearing senescent cells or other forms of damage repair.

The traditional Alzheimer's researchers, those associated with a few decades of failure to make progress towards therapies, can be pessimistic. If one talks to them, but not to the researchers running new ventures and new programs that offer real signs of progress in different approaches to treating the condition, then one comes away with the idea that everything is intractable and the field is making only slow progress, if it progresses at all. Similarly, in the bigger picture, one cannot look at the longevity industry, ignore the approach of rejuvenation through repair of damage, and come away with anything other than an incomplete view of what is taking place, an incorrect view of what is important for the future, and an incorrect view of what the plausible pace of progress might be in the years ahead.

Can We Live Longer but Stay Younger?

Where fifty years ago it was taken for granted that the problem of age was a problem of the inevitable running down of everything, entropy working its worst, now many researchers are inclined to think that the problem is "epigenetic": it's a problem in reading the information - the genetic code - in the cells. To use a metaphor of the Harvard geneticist David Sinclair, the information in each cell is digital and perfectly stored; it's the "readout," the active expression of the information, that's effectively analogue, and subject to occlusion by the equivalent of dirt and scratches on the plastic surface of a CD. Clear those off, he says, and the younger you, still intact in the information layer, jumps out - just as the younger Beatles jump out from a restored and remastered CD.

We don't have to micromanage the repair, the Harvard molecular biologist George Church observes: "If we think epigenetically, we can see that we can make the cells industriously do the repair themselves." He is among a group of engineer-entrepreneurs who are trying not to make better products for aging people but to make fewer aging people to sell products to. Perhaps aging is not a condition to be managed but a mistake to be fixed. Sinclair, for one, has successfully extended the life of yeast, and says that he is moving on to human trials. He is an evangelist for the advantages of what he calls "hormesis" - the practice of inducing metabolic stress by short intense exercise or intermittent fasting. "Every day, try to be hungry and out of breath" is his neatly epigenetic epigram.

Anti-aging research, in its "translational," or applied, form, seems to be proceeding along two main fronts: through "small molecules," meaning mostly dietary supplements that are intended to rev up the right proteins; and, perhaps more dramatically, through genetic engineering. Typically, genetic engineering involves adding or otherwise manipulating genes in a population of animals, often mice, perhaps by rejiggering a mouse's genome in embryo and then using it to breed a genetically altered strain. In mice studies, genetic modifications that cause the rodents to make greater amounts of a single protein, sirtuin 6, have resulted in longer life spans (although some scientists think that the intervention merely helped male mice to live as long as female mice).

Church and Noah Davidsohn, a former postdoc in his lab, have engaged in a secretive but much talked-about venture to make old dogs new. They have conducted gene therapy on beagles with the Tufts veterinary school, and are currently advertising for Cavalier King Charles spaniels, which are highly prone to an incurable age-related heart condition, mitral-valve disease; almost all of them develop it by the age of ten. Using a genetically modified virus, Church and Davidsohn's team will insert a piece of DNA into a dog's liver cells and get them to produce a protein meant to stop the heart disease from progressing. But the team has larger ambitions. It has been identifying other targets for gene-based interventions, studying a database of aging-related genes: genes that are overexpressed or underexpressed - that make too much or too little of a particular protein - as we grow old. In the CD replay of life, these are the notes that get muffled or amplified, and Davidsohn and Church want to restore them to their proper volume.

Many problems cling to this work, not least that there are surprisingly few "biomarkers" of increased longevity. One researcher makes a comparison with cancer research: we know a patient's cancer has been successfully treated when the cancer cells go away, but how do you know if you've made people live longer except by waiting decades and seeing when they die? Ideally, we'd find something that could be measured in a blood test, say, and was reliably correlated with someone's life span.

Church is optimistic about the genetic-engineering approach. "We know it can work because we've already had success reprogramming embryonic stem cells: you can take a really old cell and turn that back into a young cell. We're doing it now. Most of the work was done in mice, where we've extended the life of mice by a factor of two. It isn't seen as impressive, because it's mice, but now we're working on dogs. There are about nine different pathways that we've identified for cell rejuvenation, one of which eliminates senescent cells" - moldering cells that have stopped dividing and tend to spark inflammation, serving as a perpetual irritant to their neighbors.

The ability to selectively destroy senescent cells through the use of senolytic therapies doesn't make greater understanding of the biochemistry of senescent cells irrelevant, but it does mean that we don't have to wait around for that greater understanding to arrive in order for the development of therapies to get started. Destroy the bad cells now, benefit the patients now, and let the ongoing research proceed at its own pace. The open access paper here is an example of that ongoing research, an exploration of the proteins that might be important in cellular senescence in cataracts, a prominent cause of age-related blindness. Regardless of the outcome here, senolytic therapies should be under development to treat cataracts now, not later.

Senescence is a leading cause of age-related cataract (ARC). The current study indicated that the senescence-associated protein, p53, total laminin (LM), LMα4, and transforming growth factor-beta1 (TGF-β1) in the cataractous anterior lens capsules (ALCs) increase with the grades of ARC. In cataractous ALCs, patient age, total LM, LMα4, TGF-β1, were all positively correlated with p53.

In lens epithelial cell senescence models, matrix metalloproteinase-9 (MMP-9) alleviated senescence by decreasing the expression of total LM and LMα4; TGF-β1 induced senescence by increasing the expression of total LM and LMα4. Furthermore, MMP-9 silencing increased p-p38 and LMα4 expression; anti-LMα4 globular domain antibody alleviated senescence by decreasing the expression of p-p38 and LMα4; pharmacological inhibition of p38 MAPK signaling alleviated senescence by decreasing the expression of LMα4. Finally, in cataractous ALCs, positive correlations were found between LMα4 and total LM, as well as between LMα4 and TGF-β1.

Taken together, our results implied that the elevated LMα4, which was possibly caused by the decreased MMP-9, increased TGF-β1 and activated p38 MAPK signaling during senescence, leading to the development of ARC. LMα4 and its regulatory factors show potential as targets for drug development for prevention and treatment of ARC.

Link: https://doi.org/10.18632/aging.101943

In recent years, researchers have discovered a number of human gene variants or mutations that significantly lower blood cholesterol, and this also the risk of heart disease, such as DSCAML1, ANGPTL4, and ASGR1. Why does this work? Oxidized cholesterol contributes to the development of atherosclerosis with advancing age, by causing macrophages to falter in their work of removing cholesterol from blood vessel walls, become inflammatory, transform into foam cells, and die, leaving debris that grows the lesions the cells are trying to repair. Reducing overall cholesterol works because it reduces oxidized cholesterol as well.

Yet this business of reducing blood cholesterol is unfortunately far from the most efficient way to tackle atherosclerosis. It can only slow it down, and not produce significant reversal of existing fatty lesions in blood vessel walls. Nonetheless, when lowered cholesterol levels are in place for the entire lifespan rather than just as a result of statin drugs in later life, and there is a considerable prevention effect, then effect sizes can be quite large. Sadly, the mutation in APOB noted here has unpleasant side-effects that make this gene and its protein a less desirable target for therapy than the others mentioned above.

A new study finds that protein-truncating variants in the apolipoprotein B (APOB) gene are linked to lower triglyceride and LDL cholesterol levels, and lower the risk of coronary heart disease by 72 percent. Protein-truncating variants in the APOB gene are among the causes of a disorder called familial hypobetalipoproteinemia (FHBL), which causes a person's body to produce less low-density lipoproteins (LDL) and triglyceride-rich lipoproteins. People with FHBL generally have very low LDL cholesterol, but are at high risk of fatty liver disease.

"An approved drug, Mipomersen, mimics the effects of having one of these variants in APOB, but due to the risk of fatty liver disease, clinical trials for cardiovascular outcomes won't be done. Using genetics, we provided evidence that targeting this gene could reduce the risk of coronary heart disease."

The researchers sequenced the APOB gene in members of 29 Japanese families with FHBL. Eight of the Japanese families had protein-truncating variants in APOB, and individuals with one of those variants had LDL cholesterol levels 55 mg/DL lower and triglyceride levels 53 percent lower than individuals who did not have an APOB variant. The researchers also sequenced the APOB gene in 57,973 participants of a dozen coronary heart disease case-control studies of people with African, European, and South Asian ancestries, 18,442 of whom had early-onset coronary heart disease. Again, they found that people with these APOB gene variants had lower LDL cholesterol and triglyceride levels. Only 0.038 percent of the people with coronary heart disease carried an APOB variant, while 0.092 percent of those without coronary heart disease did, indicating that carrying gene variants in APOB reduces the risk of coronary heart disease.

Link: https://www.eurekalert.org/pub_releases/2019-05/buso-bfr051319.php

Immunosenescence is the name give to the age-related decline in effectiveness of the immune system. Some authors consider this to be distinct from inflammaging, the growth in chronic inflammation due to overactivation of the immune system in response to molecular damage and the presence of senescent cells, while others consider that chronic inflammation to be an aspect of immunosenescence. In today's open access paper, researchers review immunosenescence from the perspective of the adaptive immune system, here meaning detrimental changes in T cell populations. The contributing causes of these changes are given as (a) the atrophy of the thymus, (b) a growing bias towards production of myeloid rather than lymphoid cells in the bone marrow, and (c) the burden of persistent infection, particularly cytomegalovirus.

The progressive age-related atrophy of the thymus, known as thymic involution, may be the most important of these issues. Thymocytes created in the bone marrow migrate to the thymus, where they mature into T cells. As active thymic tissue is replaced with fat, the supply of new T cells diminishes. While the overall number of T cells remains much the same throughout life, these cells become increasingly dysfunctional due to a lack of replacements. Growing numbers of T cells in the old are senescent or exhausted, or uselessly specialized in large numbers to fight persistent pathogens such as cytomegalovirus. Ever fewer naive T cells capable of tackling new threats remain, and immune capability declines.

The importance of the thymus to immune aging is why, over the years, many research projects have sought to regrow and restore the thymus. Unfortunately none of these have yet resulted in reliable approaches in humans. Delivery of recombinant KGF was perhaps the most promising, given that it works very well to regrow the thymus in aged mice and non-human primates. The only human trial failed miserably, however, and no-one seems much interested in looking further into why this was the case. At the present time the closest approach to clinical application may that of Lygenesis: grow thymic tissue organoids and implant them into lymph nodes. I'm of the belief that upregulating FOXN1, a master regulator of thymic growth and function, is probably the best option, however. There is a long history of successfully achieving thymic regrowth via this method in mice, and the regulatory biochemistry appears to be the same in other mammalian species.

Immunosenescence: participation of T lymphocytes and myeloid-derived suppressor cells in aging-related immune response changes

Immunosenescence was initially defined as a group of changes that occur in the immune response during the aging process. The reason for that is the immune system was believed to collapse with the aging process, considering the increased susceptibility of these individuals to infectious diseases and developing cancer, reduced production of antibodies against specific antigens, increase in autoantibodies, decrease in T-lymphocyte proliferation, in addition to thymic involution. However, immunosenescence is currently defined by some researchers as remodeling of the immune system, suggesting plasticity of the immune system in the aging process. According to these researchers, the aging process does not necessarily bring an inevitable decline of immune functions; what happens is a rearrangement or an adaptation of the immune system to adjust the body that has been exposed to different pathogens throughout life. Depending on how successful that rearrangement or adaptation is, senior individuals can reach longevity with quality of life or, conversely, develop chronic diseases (comorbidities) and/or be often hospitalized due to severe infections.

This adaptation of the immune system brought by aging seems to result in reduced number and repertoire of T cells due to thymic involution, accumulation of memory T cells from chronic infections, homeostatic proliferation compensating for the number of naïve T cells, decreased proliferation capacity of T cells against stimuli, T cell replicative senescence and inflammaging, besides accumulation of myeloid-derived suppressor cells (MDSC).

As we get older, during hematopoiesis in the bone marrow, the myeloid lineage tends to increase, which can favor the accumulation of MDSC. These cells are able to suppress T cells proliferation and function, and produce pro-inflammatory cytokines. Moreover, there is thymus involution and replacement of thymic tissue by adipose tissue. Hence, there is reduced T cell receptor (TCR) variability and release of naïve T cells. The decreased thymic release of naïve cells, together with the immune response against infections throughout life, lead to the accumulation of memory T cells. In elderly individuals, both naïve and memory T cells can be maintained thanks to homeostatic proliferation, which shortens the telomeres of these cells, resulting in replicative senescence of T cells that produce pro-inflammatory cytokines, and promote inflammaging. The shortening of telomeres also decreases the proliferation capacity of T cells, which will produce less interleukin-2, further decreasing the proliferation of these cells.

Considering T cells are essential for the adequate response against pathogens and neoplasms, and for protection after vaccination, it seems reasonable that changes in T cells quantity, phenotype, and function play an important role in immunosenescence. By understanding each of the mechanisms originated by remodeling of the immune system brought by aging, we could use the cells addressed in the present study (T cells and MDSC) as early and minimally invasive biomarkers for aging-related diseases. The aim is to minimize the limitations of immunosenescence and ensure better treatment for the vulnerable elderly population.

In past years, there has been considerable discussion of Alzheimer's disease as a type 3 diabetes. This is by no means a formal designation, but enough papers have put forward the concept that when a new version of diabetes was in fact discovered not so long ago, it had to be designated type 4. Why call Alzheimer's a form of diabetes? Because dysregulation of insulin metabolism appears to be a feature of the condition. In the paper here, these issues with insulin signaling are linked to the generation of chronic inflammation. This makes a great deal of sense in the broader context of what is known of Alzheimer's disease, as dysregulation of immune cells in the brain, and rising levels of inflammatory signaling, are thought to arise from the presence of amyloid-β and in turn generate tau aggregates and severe pathology in the brain. In effect, inflammation bridges the early, mild stages of the condition and the later severe stages and their very different biochemistries.

Recently, type 2 diabetes mellitus (T2DM) has been identified as a risk factor for Alzheimer's disease (AD). Epidemiological studies of patient data sets have found a clear correlation between T2DM and the risk of developing AD or other neurodegenerative disorders. In one study, 85% of AD patients had diabetes or showed increased fasting glucose levels, compared to 42% in age-matched controls. In longitudinal studies of cohorts of people, it was found that glucose intolerance was a good predictor for the development of dementia later in life.

When analyzing the brain tissue of AD patients, it was observed that insulin signaling was much desensitized, even in AD patients that did not have T2DM. One study found that the levels of insulin, IGF-1, and IGF-II were much reduced in brain tissue. In addition, levels of the insulin receptor, the insulin-receptor associated PI3-kinase, and activated Akt/PKB kinase were much reduced. A second study found increased levels of IGF-1 receptors and the localization of insulin receptors within cells rather than on the cell surface where they could function.

Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common - they induce a chronic inflammation response in the brain. Insulin reduces the chronic inflammation response by inhibiting secondary cell signaling induced by pro-inflammatory cytokines. A desensitization of insulin signaling enhances the inflammation response and the desensitization observed in T2DM, therefore, not only compromises growth factor signaling, and energy utilization in the brain, but also facilitates the chronic inflammation response.

Link: https://doi.org/10.3389/fnagi.2019.00088

Levels of VCAM1 in the bloodstream increase with age, and it appears to be an important signal molecule in at least the brain. Its expression is upregulated by inflammatory cytokines, and so is a marker of inflammatory disease. Chronic inflammation of course increases with age. Researchers have shown that blocking VCAM1 can prevent suppression of neurogenesis due to delivery of old blood plasma into young mice, which is an interesting result, as one might not expect detrimental reactions to inflammatory signaling to have such a narrow bottleneck of regulation. Would a method of interfering with VCAM1 assist in tissue maintenance and cognitive function in older individuals? That remains to be determined with any certainty. The work here showing a correlation between VCAM1 and severity of Parkinson's disease, a neurodegenerative condition, reinforces the point that high levels of VCAM1 are undesirable.

There is increasing evidence that Parkinson's disease (PD) pathology is accompanied by ongoing inflammatory processess. This neuroinflammatory component is particularly relevant for better understanding disease progression accordingly developing disease-modifying therapies. Therefore, the present study explored dysregulated inflammatory profiles in the peripheral blood cells and plasma of PD patients within the context of established clinical indicators. We performed a screening of selected cell-surface chemokine receptors and adhesion molecules in peripheral blood mononuclear cells (PBMCs) from PD patients and age-matched healthy controls in a flow cytometry-based assay. ELISA was used to quantify VCAM1 levels in the plasma of PD patients.

The present data illustrate the role soluble VCAM1 (sVCAM1) levels may play in PD pathology. The levels of sVCAM1 observed here were even higher than those reported for patients with rheumatoid arthritis, multiple sclerosis, and neuromyelitis optica. Although substantial evidence exists for the association between increased sVCAM1 and age and cognitive impairment, the use of age-matched healthy donors in this study has illustrated that the increase observed in PD is independent of physiological aging. Furthermore, sVCAM1 correlated with both disease stage and the motor aspects of daily living.

Whether elevated sVCAM1 levels actively drive disease progression in PD or are a consequence of it remains to be fully understood. Of note, VCAM1 has already been implicated to be a potential mediator of PD pathogenesis. Thus, whether targeting the VCAM1-VLA4-axis is a viable therapeutic avenue remains to be established. Indeed, promising evidence for the therapeutic potential of the VCAM1-VLA4 axis in age-related pathologies of the central nervous system already exists; it has been shown that blocking VCAM1 slows down normal brain aging, induces neurogenesis, and ameliorates neuroinflammation. Our chemotaxis assay revealed diminished lymphocytic migration in PD patients which may be indicative of compromised cellular adherence and infiltration of endothelial barriers. Therefore, additional investigations and in vivo studies addressing both the expression and functional state of VCAM1 on brain endothelial cells are necessary.

Link: https://doi.org/10.1186/s12974-019-1482-8

What are the important steps in the progression of neurodegenerative diseases characterized by the presence of protein aggregates? These aggregates are misfolded or otherwise altered proteins that precipitate to form solid deposits. This means α-synuclein in the case of Parkinson's disease, or amyloid-β and tau in the cause of Alzheimer's disease, to pick the best known examples. A growing body of evidence is pointing to dysfunction and inflammation in the immune cells known as microglia, a type of macrophage resident in the central nervous system. Like macrophages elsewhere in the body, microglia are responsible for chasing down pathogens and clearing up debris. They also participate in a range of other supporting activities that assist the function of neurons.

In Alzheimer's disease, there is compelling evidence for microglia to be driven into an inflammatory state by the presence of amyloid-β. They act as the bridge between the mild earlier stage of the condition, in which amyloid-β accumulates, and the later stage in which tau aggregates form and neurons die. It is the chronic inflammation and dysfunction of microglia in brain tissue that drives this more severe tau pathology. Inflammatory behavior in microglia appears to involve significant numbers of senescent microglia, and researchers have shown that removing these senescent cells can turn back tau pathology in mouse models and reduce levels of neuroinflammation. Lingering senescent cells of any cell type cause harm through secreting inflammatory and other signals, the senescence-associated secretory phenotype (SASP). This actively maintains a disordered tissue environment, and we'd all benefit from its removal in old age.

Given that microglia have this role in Alzheimer's disease, are they also causing similar issues in other neurodegenerative disease processes? Most likely yes. The article here examines the role of microglia in α-synuclein aggregation, an important part of the progression of Parkinson's disease. This continues to add support for the idea that senolytic therapies, capable of removing senescent cells and dampening the inflammation that they cause, will prove to be a useful treatment for neurodegenerative conditions. Indeed, they should be a useful preventative treatment prior to the advent of neurodegenerative disease. Chronic inflammation drives many of the common diseases of aging, and to the extent that the causes of that inflammation can be prevented, then age-related disease - and aging itself - will be pushed back.

Do Immune Cells Promote the Spread of α-Synuclein Pathology?

How does α-synuclein pathology spread? Researchers say immune cells bear some of the blame. Certain types of inflammation in the intestine modulate α-synuclein accumulation there. In mice, experimental colitis at a young age accelerated α-synuclein pathology in the brain 18 months later, consistent with the idea that misfolded protein can travel from gut to brain. Other research implicates brain immune cells in propagation. Mutant α-synuclein oligomers that were incapable of forming fibrils still stimulated aggregation in brain. They appeared to work their mischief by firing up inflammation, suggesting that microglia somehow mediate α-synuclein spread.

First, peripheral immunity. Scientists know that intestinal infections or inflammation can pump up α-synuclein production in the gut, perhaps as part of an antimicrobial defense. This strengthened the idea that Parkinson's disease might start in the intestine and travel from there to the brain. People who suffer from inflammatory bowel disorders are at elevated risk of Parkinson's disease, and genetic studies have found shared risk between the two. While the links are suggestive, no one had yet shown directly that gut inflammation triggered brain pathology.

Researchers provoked colitis in 3-month-old transgenic α-synuclein mice by adding dextran sulfate sodium (DSS) to their water. This irritant caused macrophages to invade the lining of the gut wall. In response, enteric neurons lying just below the mucosa, in the submucosal plexus, began to accumulate α-synuclein. The researchers aged the mice to 12 or 21 months. At 12 months, they saw no difference between the brains of control transgenics and those that had colitis as youngsters. By 21 months, however, the colitis group had six times more α-synuclein aggregates in brainstem regions than controls did. These mice had but half as many dopaminergic neurons as controls, suggestive of neurodegeneration.

Researchers are also interested in how α-synuclein aggregates propagate within the brain. When researchers injected aggregated material into mouse brain, it was quickly cleared to undetectable levels. Then, after an incubation period, aggregates appeared and spread through brain. The leading theory holds that this occurs through templated seeding of endogenous α-synuclein by the injected aggregates. To test this idea, researchers used a mutant form of α-synuclein, V40G, that forms unstructured oligomers but is incapable of forming fibrils. In a test tube, V40G blocks fibrillization of wild-type α-synuclein as well. Thus, this form should prevent templated seeding in vivo.

The researchers injected either V40G or wild-type α-synuclein into the striata of wild-type mice. To their surprise, V40G seeded aggregates even better than wild-type α-synuclein did. Four weeks after injection, mice that had received V40G had far more α-synuclein pathology in the rhinal cortex than did mice treated with wild-type protein. Why might this be? The researchers analyzed gene expression in injected brains to glean clues. They found heightened inflammatory and innate immune responses in V40G-treated animals relative to those treated with wild-type α-synuclein. Supporting this, levels of the inflammatory cytokine IL-1β shot up in numerous brain regions after V40G administration, and this spike preceded the spread of α-synuclein aggregates to these regions. Treating mice with the anti-inflammatory drug lenalidomide along with V40G prevented this spike in IL-1β.

Based on these findings, researchers proposed a new model of α-synuclein propagation. Perhaps α-synuclein oligomers kick off microglial activation and cytokine release, and this inflammatory microenvironment then aggravates nearby neurons, causing α-synuclein to clump up in their cell bodies. By this logic, rather than α-synuclein aggregates passing directly from neuron to neuron, microglia would be essentially the conveyor belt for α-synuclein pathology.

Mitochondria, the power plants of the cell, carry their own DNA, encoding a few proteins essential to mitochondrial operation. Mutational damage to these genes can result in broken mitochondria that take over cells and cause the export of oxidizing molecules, contributing to the progression of aging. Not all mitochondrial DNA damage is the same, however: point mutations versus deletion mutations, for example. Researchers have struggled to produce consistent data in mice and nematodes with increased levels of mitochondrial DNA damage of various sorts. Some mice engineered to have greater mutation rates in mitochondrial DNA exhibit accelerated aging, while others do not, with little sign of a coherent explanation as to why beyond the sentiment that short-lived species are not useful models in this case.

The work here in nematodes, using radiation to produce mitochondrial DNA damage, should probably taken as more in the same vein. The researchers find no correlation between damage levels and life span, and this may well be because they are not introducing the right sort of mutational damage that occurs over the course of aging in longer-lived species. It is thought that deletion mutations, or other equally drastic damage, is necessary, for example. But nematodes do not accumulate such damage over the course of their very short lives. They may just be a very poor model for any consideration of the mitochondrial contribution to the aging process.

The mitochondrial free radical theory of aging (mFRTA) proposes that accumulation of oxidative damage to macromolecules in mitochondria is a causative mechanism for aging. Accumulation of mitochondrial DNA (mtDNA) damage may be of particular interest in this context. While there is evidence for age-dependent accumulation of mtDNA damage, there have been only a limited number of investigations into mtDNA damage as a determinant of longevity. This lack of quantitative data regarding mtDNA damage is predominantly due to a lack of reliable assays to measure mtDNA damage.

Here, we report adaptation of a quantitative real-time polymerase chain reaction (qRT-PCR) assay for the detection of sequence-specific mtDNA damage in C. elegans and apply this method to investigate the role of mtDNA damage in the aging of nematodes. We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in reactive oxygen species detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found that there is no simple relationship between mtDNA damage and lifespan.

In order to more directly test the relevance of mtDNA damage in the context of lifespan determination, we introduce damage to mtDNA directly by exposing young C. elegans to UV- or γ-radiation. Sufficiently high levels of UV-radiation cause extensive mtDNA damage and this indeed shortened C. elegans lifespan. However, we found that lower levels of this stressor still significantly increase mtDNA damage but without causing significant detriments and that some levels even resulted in lifespan extension and healthspan improvements.

This is consistent with the concept of hormesis; that exposure to mild stress, through evoking adaptive responses and strengthening stress defense mechanisms can lead to lifespan extension. However, it is worth noting that in our experiments, even under conditions where UV damage results in hormetic benefits, damage remained detectably elevated, even on the day following exposure. The lack of evidence for a tight relationship between mtDNA damage burden and lifespan in C. elegans is consistent with our recent finding that, most likely due to the short lifespan of nematodes, mtDNA deletion do not accumulate with age in C. elegans.

Link: https://doi.org/10.3389/fgene.2019.00311

Intelligent people tend to have a longer life expectancy. Is this because they also tend to have more education, be wealthier, and make better lifestyle choices? This web of correlations is hard to untangle. Might there also be underlying physical mechanisms that contribute to this well known association between intelligence and long-term health, however? Are more intelligent people a little more physically robust, on average? There is some evidence for this sort of effect to be present in other species, and some genetic studies suggest that common variants affect both traits, while twin studies also add evidence in favor of physical mechanisms that influence both intelligence and longevity.

Here, researchers argue that variations in mitochondrial function is the mechanism of greatest interest in this matter, as this can affect the energy-hungry tissues of both brain and heart muscle. Mitochondria are the power plants of the cell, packaging chemical energy store molecules to power cellular processes. It is well known that mitochondrial function is important in aging, and declines with age. If an individual has a slightly more efficient mitochondrial population, or mitochondria that are just a little more resilient to the molecular damage of aging, perhaps that will be enough for both improved brain function throughout development and adult life, and a slower decline into age-related disease and mortality.

For over 100 years, scientists have sought to understand what links a person's general intelligence, health and aging. In a new study, scientists suggest a model where mitochondria, or small energy producing parts of cells, could form the basis of this link. This insight could provide valuable information to researchers studying various genetic and environmental influences and alternative therapies for age-related diseases, such as Alzheimer's disease. "There are a lot of hypotheses on what this link is, but no model to link them all together. Mitochondria produce cellular energy in the human body, and energy availability is the lowest common denominator needed for the functioning of all biological systems. My model shows mitochondrial function might help explain the link between general intelligence, health, and aging."

The insight came while working on a way to better understand gender-specific vulnerabilities related to language and spatial abilities with certain prenatal and other stressors, which may also involve mitochondrial functioning. Mitochondria produce ATP, or cellular energy. They also respond to their environment, so habits such as regular exercise and a diet with fruits and vegetables can promote healthy mitochondria. "These systems are being used over and over again, and eventually their heavy use results in gradual decline. Knowing this, we can help explain the parallel changes in cognition and health associated with aging. Also with good mitochondrial function, the aging processes will occur much more slowly. Mitochondria have been relatively overlooked in the past, but are now considered to relate to psychiatric health and neurological diseases. Chronic stress can also damage mitochondria and that can affect the whole body - such as the brain and the heart - simultaneously."

Link: https://munews.missouri.edu/news-releases/2019/0508-intelligence-can-link-to-health-and-aging-mu-study-finds/

It is quite easy to find correlations between the many varied aspects of aging. People age at different rates, largely due to differences in lifestyle choices: exercise, calorie intake, smoking, and so forth. Genetics are less of an influence. While there is tremendous interest in the genetics of aging, I have to think that this is something of a case of a hammer in search of a nail. This is an era of genetic technologies and genetic data, in which the cost of the tools has fallen so low and the scope of the capabilities has expanded so greatly that everyone is tempted to use it in every possible circumstance. Yet outside of the unlucky minority who suffer severe inherited mutations, genetic variations only become important in later life, and even then the contribution of genetics to life expectancy is much smaller than that of lifestyle choices.

Nonetheless, the point is that different people age at different rates. For any given person, however, the many aspects of aging are fairly consistent with one another - nothing races ahead in isolation. Aging is a body-wide phenomenon of multiple processes of damage accumulation that proceed in an entangled fashion, feeding one another and all contributing to systemic downstream consequences, such as chronic inflammation or vascular dysfunction. In this sort of a system, if any one organ or biological system is more aged and damaged in a given individual, then it is very likely that all of the others are as well. This works for correlations with mortality as well as specific age-related diseases or metrics.

In the research results noted below, a poor sense of smell in older individuals correlates with a significantly raised risk of mortality over a ten year horizon. For the reasons given above, this shouldn't be terrible surprising. Loss of sense of smell is a reflection of levels of neurodegeneration, loss of function in the brain. That in turn tends to match up with loss of function elsewhere in the body, particularly in the cardiovascualar system. Failing sense of smell is further specifically associated with Alzheimer's disease, as the olfactory system in the brain is where the condition starts. You can look at the work of Leucadia Therapeutics for evidence that Alzheimer's disease begins in this way because clearance of cerebrospinal fluid in that part of the brain is impaired with age, leading to increased molecular waste and cellular dysfunction.

Poor Sense of Smell and Risk for Death in Older Adults

Many older adults have a poor sense of smell, which can affect their appetite, safety, and quality of life. It is also associated with increased risk for death and may be an early sign of some diseases, like Alzheimer's disease and Parkinson's disease. Most previous studies have studied people with a poor sense of smell for relatively short periods of time, and they did not examine whether there are differences by race or sex. We also need a better understanding of the factors that might explain the relationship between poor sense of smell and increased risk for death.

Researchers analyzed data on the members of an ongoing study that was done in 2 communities in the United States (Memphis, Tennessee, and Pittsburgh, Pennsylvania). There were 2289 adults, aged 71 to 82 years, at baseline. The participants completed a Brief Smell Identification Test (BSIT). As part of the test, they smelled 12 common odors and were asked to identify each odor from 1 of 4 options. Each correct response was given a point. Using the BSIT scores, the researchers classified the participants as having good, moderate, or poor sense of smell. Participants attended several clinical study visits, where they were examined and had cognitive tests. In these visits, patients were identified as having dementia or Parkinson's disease, and staff measured participants' body weights. The main end points for the study were death from any cause; death from dementia or Parkinson's disease; and death from cardiovascular disease, cancer, or respiratory causes.

A poor sense of smell was associated with older age, male sex, black race, alcohol drinking, and smoking. It was also associated with dementia, Parkinson's disease, and chronic kidney disease. Participants with a poor sense of smell had a nearly 50% higher risk for death at 10 years. A poor sense of smell was also associated with increased risk for death from dementia or Parkinson's disease and death from cardiovascular disease. The investigators did some exploratory statistical analyses and found that weight loss and a history of dementia or Parkinson's disease could explain only part of the relationship between poor sense of smell and death.

Relationship Between Poor Olfaction and Mortality Among Community-Dwelling Older Adults: A Cohort Study

To assess poor olfaction in relation to mortality in older adults and to investigate potential explanations, 2289 adults aged 71 to 82 years at baseline underwent the Brief Smell Identification Test in 1999 or 2000 (baseline). All-cause and cause-specific mortality was assessed at 3, 5, 10, and 13 years after baseline. During follow-up, 1211 participants died by year 13. Compared with participants with good olfaction, those with poor olfaction had a 46% higher cumulative risk for death at year 10 and a 30% higher risk at year 13.

However, the association was evident among participants who reported excellent to good health at baseline but not among those who reported fair to poor health. In analyses of cause-specific mortality, poor olfaction was associated with higher mortality from neurodegenerative and cardiovascular diseases. Mediation analyses showed that neurodegenerative diseases explained 22% and weight loss explained 6% of the higher 10-year mortality among participants with poor olfaction.

Efficient DNA repair is necessary to prevent cells from becoming dysfunctional or senescent in response to stochastic nuclear DNA damage. This is particularly important in stem cell populations, as there is no outside source to replace their losses, or repair persistent dysfunction. Researchers here note that the DNA damage response fails to trigger sufficiently in old intestinal stem cell populations, and this may be an underlying contributing cause of higher levels of cellular senescence in these cells.

Aging is related to disruption of tissue homeostasis, which increases the risks of developing inflammatory bowel diseases (IBDs), and colon cancer. However, the molecular mechanisms underlying this process are largely unknown. Various age-related dysfunctions of adult tissue-resident stem/progenitor cells (TSCs, also known as somatic stem cells) are associated with perturbation of tissue homeostasis. Restoration of stem cell functions has attracted much attention as a promising therapeutic strategy for geriatric diseases.

The intestinal epithelium is one of the most rapidly renewing tissues in the body. Lgr5-expressing intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. Therefore, dysfunction of ISCs may be important for the disruption of intestinal homeostasis and subsequent induction of functional disorders. However, the influence of aging on the functions of ISCs and induction of diseases is largely unknown.

Recent studies demonstrated that accumulation of senescent cells promotes organismal aging. Cells become senescent in response to various aging stresses, such as oxidative stress, telomere shortening, inflammation, irradiation, exposure to chemicals, and the mitotic stress, all of which induce DNA damage. Numerous types of DNA damage occur naturally and are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. The mutation rate is highest in the small and large intestines. However, the influence of aging on the DDR in ISCs has not been studied.

Here, we compared induction of the DDR, inflammation, and mitochondrial biogenesis upon irradiation between young and old mouse ISCs in vivo. Induction of the DDR and expression of associated proteins were decreased in old ISCs. The DDR was sustained in old differentiated cells, suggesting that only the responsiveness to DNA damage was perturbed and DDR capacity was potentially sustained in old ISCs. Our results suggest that the competence of the DDR in ISCs declines with age in vivo.

Link: https://doi.org/10.1186/s41232-019-0096-y

There is a strong association in mammalian species between metabolic rate, size, and life span. When pulling in bird species to compare, however, it is observed that they tend to have higher metabolic rates and longer life spans at a given size. So the question here is what exactly is going on in bird metabolism that allows for this more heated operation of cellular metabolism, necessary to meet the demands of flight, without the consequences to life span observed in mammalian species. The open access paper here is illustrative of research in this part of the comparative biology of aging field. Is there anything in this ongoing work on metabolism and aging that might one day lead to methods of extending mammalian life? Perhaps, perhaps not. Altering the operation of metabolism is a poor second best to repairing the damage that causes aging, but one never knows what might emerge from fundamental research at the end of the day.

Mitonuclear communication is at the heart of metabolic regulation, especially in fundamental processes such as cellular respiration. All endothermic organisms have evolved high metabolic rates for increased heat production. However, birds and mammals evolved endothermy independently of each other, and demonstrate some stark differences. Birds live significantly longer lives compared with mammals of similar body size, despite having higher metabolic rates, body temperatures, and blood glucose concentration.

The underlying physiological mechanisms that explain differences between mammals and birds are varied, and include differences at tissue- and cell-levels. For both of these groups, mass-specific basal metabolic rate (BMR) decreases with body size and body size accounts for much of the variation in BMR, however, much variation among species still remains to be explained. Because BMR is defined fundamentally as the sum of tissue metabolic rates, it follows that variation in BMR may relate to the relative size of central organs.

Alternatively, cellular machinery of the tissues of birds and mammals may differ. Metabolic intensity of tissues is thought to vary because of differences in numbers of mitochondria within cells, concentrations of metabolic enzymes, activity or quantity of the membrane sodium-potassium ATPase pump, and the number of double bonds in fatty acids of cell membranes. Because of differences in whole-organism metabolic rate, we may also expect differences within the rates of cellular processes, including oxidative stress.

Oxidative stress is a balance, inherent to all aerobic organisms, between the potential damage that could be accrued by reactive oxygen species (ROS) and the resources cells have to thwart that damage through the antioxidant system. This process has gained momentum in the ecological physiology literature because it has been implicated in determining rates of aging. Here, we sought to quantify parts of the oxidative stress system in a diverse group of birds and mammals. Our question was two-fold: does oxidative stress (a product of aerobic respiration and thus BMR) scale with body mass in these two groups? And are there differences in oxidative stress between birds and mammals?

Our first finding is that cellular metabolism and every parameter that we measured to quantify oxidative stress in birds and mammals does not scale with body mass. This implies that differences at the cellular level might make small contributions to scaling at the organ level, pointing to the fact that scaling of metabolism may reside in higher levels of organization. An obvious explanation may be that organ sizes between similarly-sized birds and mammals may be disproportionally larger in birds compared with mammals, leading to higher BMR.

Secondly, birds showed significantly lower basal cellular oxygen consumption, lipid oxidative damage, and lower activities of catalase. These results together imply several possible physiological mechanisms, none of which are mutually exclusive: (i) birds may have cells with significantly fewer mitochondria or with mitochondria that are more uncoupled; (ii) birds may be less burdened by ROS production compared with mammals; or (iii) birds may have membranes with lower membrane polyunsaturation compared with mammals.

Link: https://doi.org/10.1093/icb/icz017