Something to think about for today: SENS, the Strategies for Engineered Negligible Senescence is not put forward as a theory of aging, but it is a theory of aging, one that pulls from many other partial attempts to explain aging. It purports to describe, as best we know, the detailed mechanisms that lie at the root of degenerative aging - but is presented (and currently running) as a program of research and development to reverse aging. That is the testable part of the theory, if you like: implement SENS and we should see rejuvenation. If this comes to pass, then it is true that SENS as laid out at present does describe all forms of fundamental damage that cause aging. If not, then SENS is either wrong or, more likely, incomplete - there is some other form of damage that is important and unconnected to those already discovered.

(No new form of fundamental change or damage related to aging has been identified in the past 25 years, across a time of raging progress in biotechnology, which should gives us some confidence that there are no others. There is always room to argue, however, and science is anything but static).

There are, it has to be said, a great many theories of aging. Following this line of thinking, it occurs to me that we can classify most theories of aging according to where they stand with respect to the hole we find ourselves in - that hole being the inconvenient fact that we're all aging to death, and progressively increasing suffering and pain lies in each of our personal futures.

I see three broad buckets for this hole-based taxonomy:

• How did we get into this hole?
• What is going on in here?
• How do we get out of this hole?

How did we get into this hole?

Evolutionary theories of aging seek to explain how we came to age the way we do. Here the proposed mechanisms of aging inform the discussion and modeling of plausible evolutionary processes that would produce them - as well as the staggering variety in lifespan and pace of aging that exists in the natural world. I see this as scientific dispassion at its finest: "Look at the interesting way in which we're all dying! Fascinating, no? We should take some time to think about how this came to pass."

What is going on in here?

Other theories of aging focus on modeling how aging happens: what are the exact mechanisms? Many different approaches to these theories exist. Consider, for example, those that describe aging at the high level, such as in the use of reliability theory to frame aging in the form of a systems failure model. At the other end of the room we have things like the mitochondrial free radical theory of aging, which proposes detailed and particular mechanisms in cells and cellular components that lead to damage and then the larger-scale manifestations of aging.

How do we get out of this hole?

So here we return to SENS, a meta-theory of aging that pulls from many of the mechanism-focused theories of aging proposed over the past century. Until the advent of SENS there really wasn't any sort of contingent in the scientific community whose members presented a theory of aging as something more like a theory on how to defeat aging - to prevent and treat aging with therapies, reverse frailty in the old by removing its root causes, and stop the young from becoming aged.

So we are in a hole, no arguing that. Getting out does require some understanding of the hole in order to best direct efforts - but the scientific community is far and away past the point at which we could be effectively working our way out. Spending all our time gathering more knowledge is no longer good strategy. We in fact don't need to know all that much about how we got here, nor exactly how fundamental causes of aging spiral outward to create the thousand and one causes of death we observe in old people. What SENS tells us is that we just need to know what those root causes are and how to fix them. Additional information is useful, and will probably improve efficiency, but it is not absolutely necessary and nowhere near as important as just forging ahead to get the job done. The test of SENS as a theory aging is for the research community to get out there and actually fix the problems that are killing us.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Some interesting results from genetic research: scientists "have shown definitively that a small number of places in the human genome are associated with a large number and variety of diseases. In particular, several diseases of aging are associated with a locus which is more famous for its role in preventing cancer. For this analysis, [researchers] cataloged results from several hundred human Genome-Wide Association Studies (GWAS) from the National Human Genome Research Institute. These results provided an unbiased means to determine if varied different diseases mapped to common 'hotspot' regions of the human genome. This analysis showed that two different genomic locations are associated with two major subcategories of human disease. ... More than 90 percent of the genome lacked any disease loci. Surprisingly, however, lots of diseases mapped to two specific loci, which soared above all of the others in terms of multi-disease risk. The first locus at chromosome 6p21, is where the major histocompatibility (MHC) locus resides. The MHC is critical for tissue typing for organ and bone marrow transplantation, and was known to be an important disease risk locus before genome-wide studies were available. Genes at this locus determine susceptibility to a wide variety of autoimmune diseases ... The second place where disease associations clustered is the INK4/ARF (or CDKN2a) tumor suppressor locus [also known as p16]. This area, in particular, was the location for diseases associated with aging: atherosclerosis, heart attacks, stroke, Type II diabetes, glaucoma and various cancers. ... The finding that INK4/ARF is associated with lots of cancer, and MHC is associated with lots of diseases of immunity is not surprising - these associations were known. What is surprising is the diversity of diseases mapping to just two small places: 30 percent of all tested human diseases mapped to one of these two places. This means that genotypes at these loci determine a substantial fraction of a person's resistance or susceptibility to multiple independent diseases. ... In addition to the MHC and INK4/ARF loci, five less significant hotspot loci were also identified. Of the seven total hotspot loci, however, all contained genes associated with either immunity or cellular senescence. Cellular senescence is a permanent form of cellular growth arrest, and it is an important means whereby normal cells are prevented from becoming cancerous. It has been long known that senescent cells accumulate with aging, and may cause aspects of aging. This new analysis provides evidence that genetic differences in an individual's ability to regulate the immune response and activate cellular senescence determine their susceptibility to many seemingly disparate diseases."

Link: http://news.unchealthcare.org/news/2012/september/diseases-of-aging-map-to-a-few-hotspots-on-the-human-genome

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A comprehensive understanding of the brain is an important line item for future medical development, as the research community will have to develop ways to repair the brain and reverse aspects of its aging while preserving the structures that encode the mind. Here is a look at one of the higher profile projects of recent years: "Paul Allen, the 59-year-old Microsoft cofounder [has] plowed $500 million into the Allen Institute for Brain Science, a medical Manhattan Project that he hopes will dwarf his contribution as one of the founding fathers of software. The institute, scattered through three buildings in Seattle's hip Fremont neighborhood, is primarily focused on creating tools, such as the mouse laser, which is technically a new type of microscope, that will allow scientists to understand how the soft, fleshy matter inside the human skull can give rise to the wondrous, mysterious creative power of the human mind. ... His first $100 million investment in the Allen Institute resulted in a gigantic computer map of how genes work in the brains of mice, a tool that other scientists have used to pinpoint genes that may play a role in multiple sclerosis, memory and eating disorders in people. Another $100 million went to creating a similar map of the human brain, already resulting in new theories about how the brain works, as well as maps of the developing mouse brain and mouse spinal cord. These have become essential tools for neuroscientists everywhere. Now Allen, the 20th-richest man in America, with an estimated net worth of $15 billion, has committed another $300 million for projects that will make his institute more than just a maker of tools for other scientists, hiring several of the top minds in neuroscience to spearhead them. One effort will try to understand the mouse visual cortex as a way to understand how nerve cells work in brains in general. Other projects aim to isolate all the kinds of cells in the brain and use stem cells to learn how they develop. Scientists think there may be 1,000 of these basic building blocks, but they don't even know that. 'In software,' Allen says, 'we call it reverse engineering.'"

Link: http://www.forbes.com/sites/matthewherper/2012/09/18/inside-paul-allens-quest-to-reverse-engineer-the-brain/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A few days back, I pointed out research that indicates brain cells increasingly become senescent with age. This is a challenge: we want to get rid of senescent cells and prevent their buildup because the harm they cause contributes to degenerative aging, but the obvious way to do that is through targeted destruction via one of the many types of cell-targeting and cell-killing technologies presently under development. This is fine and well for tissues like skin and muscle, in which cells turn over and are replaced - but in the brain and nervous system there are many small but vital populations of cells that are never replaced across the normal human life span. The cells you are born with last a lifetime, and some fraction of those cells contain the data that makes up the mind.

Thus it begins to seem likely that we can't just rampage through and destroy everything that looks like a senescent cell: possible therapies to address cell senescence as a contribution to aging will have to be more discriminating, and so more complex and costly to develop.

Following on in this topic, I noticed an open access paper today that examines the role of cellular senescence of astrocyte, the support cells of the brain, in Alzheimer's disease (AD). Unlike the research I noted above, the biochemical signatures of senescence examined here are the same as those used in last year's mouse study showing benefits resulting from a (necessarily) convoluted way of destroying senescent cells as they emerge - which of course starts the mind wandering on what might be going on in the brain of these mice. Astrocytes can perhaps be replaced without harming the mind or important nervous cells, but what about other cells in the brain?

In any case, here is the paper:

Astrocyte Senescence as a Component of Alzheimer's Disease

A recent development in the basic biology of aging, with possible implications for AD, is the recognition that senescent cells accumulate in vivo. Although senescent cells increase with age in several tissues, little is known about the potential appearance of senescent cells in the brain. The senescence process is an irreversible growth arrest that can be triggered by various events including telomere dysfunction, DNA damage, oxidative stress, and oncogene activation. Although it was once thought that senescent cells simply lack function, it is now known that senescent cells are functionally altered. They secrete cytokines and proteases that profoundly affect neighboring cells, and may contribute to age-related declines in organ function.

...

Astrocytes comprise a highly abundant population of glial cells, the function of which is critical for the support of neuronal homeostasis. ... Impairment of these functions through any disturbance in astrocyte integrity is likely to impact multiple aspects of brain physiology. Interestingly, astrocytes undergo a functional decline with age in vivo that parallels functional declines in vitro. We demonstrated that in response to oxidative stress and exhaustive replication, human astrocytes activate a senescence program.

...

The importance of senescent astrocytes in age-related dementia has been the subject of recent discussion, but to date, there is little evidence to suggest that senescent astrocytes accumulate in the brain. In this study, we examined brain tissue from aged individuals and patients with AD to determine whether senescent astrocytes are present in these individuals. Our results demonstrate that senescent astrocytes accumulate in aged brain, and further, in brain from patients with AD.

Furthermore, since A? peptides induce mitochondrial dysfunction, oxidative stress, and alterations in the metabolic phenotype of astrocytes; we examined whether A? peptides initiate the senescence response in these cells. In vitro, we found that exposure of astrocytes to A?1-42 triggers senescence and that senescent astrocytes produce high quantities of interleukin-6 (IL-6), a cytokine known to be increased in the [central nervous system] of AD patients. Based on this evidence, we propose that accumulation of senescent astrocytes may be one age-related risk factor for sporadic AD.

As I mentioned in the last post on this subject, this all seems to point to the likely need for ways to reverse cellular senescence, not just selectively destroy senescent cells - at least for some populations of nerve cells. One open question here is whether fixing all the known fundamental forms of cellular damage (as described in the Strategies for Engineered Negligible Senescence) would be sufficient to achieve this end.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A few days back, I pointed out research that indicates brain cells increasingly become senescent with age. This is a challenge: we want to get rid of senescent cells and prevent their buildup because the harm they cause contributes to degenerative aging, but the obvious way to do that is through targeted destruction via one of the many types of cell-targeting and cell-killing technologies presently under development. This is fine and well for tissues like skin and muscle, in which cells turn over and are replaced - but in the brain and nervous system there are many small but vital populations of cells that are never replaced across the normal human life span. The cells you are born with last a lifetime, and some fraction of those cells contain the data that makes up the mind.

Thus it begins to seem likely that we can't just rampage through and destroy everything that looks like a senescent cell: possible therapies to address cell senescence as a contribution to aging will have to be more discriminating, and so more complex and costly to develop.

Following on in this topic, I noticed an open access paper today that examines the role of cellular senescence of astrocyte, the support cells of the brain, in Alzheimer's disease (AD). Unlike the research I noted above, the biochemical signatures of senescence examined here are the same as those used in last year's mouse study showing benefits resulting from a (necessarily) convoluted way of destroying senescent cells as they emerge - which of course starts the mind wandering on what might be going on in the brain of these mice. Astrocytes can perhaps be replaced without harming the mind or important nervous cells, but what about other cells in the brain?

In any case, here is the paper:

Astrocyte Senescence as a Component of Alzheimer's Disease

A recent development in the basic biology of aging, with possible implications for AD, is the recognition that senescent cells accumulate in vivo. Although senescent cells increase with age in several tissues, little is known about the potential appearance of senescent cells in the brain. The senescence process is an irreversible growth arrest that can be triggered by various events including telomere dysfunction, DNA damage, oxidative stress, and oncogene activation. Although it was once thought that senescent cells simply lack function, it is now known that senescent cells are functionally altered. They secrete cytokines and proteases that profoundly affect neighboring cells, and may contribute to age-related declines in organ function.

...

Astrocytes comprise a highly abundant population of glial cells, the function of which is critical for the support of neuronal homeostasis. ... Impairment of these functions through any disturbance in astrocyte integrity is likely to impact multiple aspects of brain physiology. Interestingly, astrocytes undergo a functional decline with age in vivo that parallels functional declines in vitro. We demonstrated that in response to oxidative stress and exhaustive replication, human astrocytes activate a senescence program.

...

The importance of senescent astrocytes in age-related dementia has been the subject of recent discussion, but to date, there is little evidence to suggest that senescent astrocytes accumulate in the brain. In this study, we examined brain tissue from aged individuals and patients with AD to determine whether senescent astrocytes are present in these individuals. Our results demonstrate that senescent astrocytes accumulate in aged brain, and further, in brain from patients with AD.

Furthermore, since A? peptides induce mitochondrial dysfunction, oxidative stress, and alterations in the metabolic phenotype of astrocytes; we examined whether A? peptides initiate the senescence response in these cells. In vitro, we found that exposure of astrocytes to A?1-42 triggers senescence and that senescent astrocytes produce high quantities of interleukin-6 (IL-6), a cytokine known to be increased in the [central nervous system] of AD patients. Based on this evidence, we propose that accumulation of senescent astrocytes may be one age-related risk factor for sporadic AD.

As I mentioned in the last post on this subject, this all seems to point to the likely need for ways to reverse cellular senescence, not just selectively destroy senescent cells - at least for some populations of nerve cells. One open question here is whether fixing all the known fundamental forms of cellular damage (as described in the Strategies for Engineered Negligible Senescence) would be sufficient to achieve this end.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A nice demonstration of the degree to which the pace of aging is inherited - but remember that for the vast majority of us, lifestyle choices have more influence than genes, while progress in medical technology trumps all such concerns: "Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI(34) scores were computed from 34 common health variables and compared between the two groups. The FI(34) was better correlated than chronological age with mortality. The mean FI(34) value of the OSLP was 31% higher than that of the OLLP. The FI(34) increased exponentially, at an instantaneous rate that accelerated 2.0% annually in the OLLP and 2.7 % in the OSLP consequently yielding a 63% larger accumulation in the latter group. The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, [sibling pairs] were significantly correlated regarding FI(34) scores, and heritability of the FI(34) was estimated to be 0.39. ... Variation in the FI(34) is, in part, due to genetic variation; thus, the FI(34) can be a phenotypic measure suitable for genetic analyses of healthy aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22986583

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm