Category Archives: Longevity Medicine

Building patches for damaged hearts is a popular implementation in tissue engineering at the moment: it's an achievable stepping stone on the way to more complex goals, such as the creation of entire organs starting from only a patient's stem cells, something that still lies in the future. Progress towards a long-term goal in any field requires useful intermediary products, as they help pull in the greater support and funding needed for the next phase of research and development.

When heart cells die from lack of blood flow during a heart attack, replacing those dead cells is vital to the heart muscle's recovery. But muscle tissue in the adult human heart has a limited capacity to heal, which has spurred researchers to try to give the healing process a boost. Various methods of transplanting healthy cells into a damaged heart have been tried, but have yet to yield consistent success in promoting healing.

Now, [researchers] have developed a patch composed of structurally modified collagen that can be grafted onto damaged heart tissue. Their studies in mice have demonstrated that the patch not only speeds generation of new cells and blood vessels in the damaged area, it also limits the degree of tissue damage resulting from the original trauma. The key [is] that the patch doesn't seek to replace the dead heart-muscle cells. Instead, it replaces the epicardium, the outer layer of heart tissue, which is not muscle tissue, but which protects and supports the heart muscle, or myocardium.

The epicardium - or its artificial replacement - has to allow the cell migration and proliferation needed to rebuild damaged tissue, as well as be sufficiently permeable to allow nutrients and cellular waste to pass through the network of blood vessels that weaves through it. The mesh-like structure of collagen fibers in the patch has those attributes, serving to support and guide new growth. Because the patch is made of acellular collagen, meaning it contains no cells, recipient animals do not need to be immunosuppressed to avoid rejection. With time, the collagen gets absorbed into the organ.

Link: http://www.eurekalert.org/pub_releases/2013-08/sumc-scp082613.php

Source:
https://www.fightaging.org/archives/2013/08/a-collagen-patch-to-spur-heart-tissue-repair.php

Mammalian (or mechanistic, depending on who you ask) target of rapamycin (mTOR) is the most likely candidate for the next round of billion-dollar research funding devoted to the search for drugs that can slow aging. It will be a repeat of the overhyped and ultimately largely futile interest in sirtuin research, which generated knowledge but nothing of real practical application, except that this time there is far more compelling evidence that manipulation of mTOR actually extends life in laboratory animals. Though as always, there are those who believe that this is not in fact the case - that mTOR alteration only reduces cancer risk, rather than impacting the processes of aging per se. Just as resveratrol and resveratrol-derivatives are the compounds of choice for those investigating sirtuin biology, so rapamycin and rapamycin-derivatives are the compounds of choice for research groups focused on manipulating mTOR and its related signaling networks. I would imagine that we're in for another decade or so of overhyped claims and public and research community interest in what is in fact an inefficient, expensive, and time-consuming path towards only slightly extending healthy life.

Drugs to slow aging through alterations to metabolism are not the path to radical life extension. Slowing aging does nothing for people already old. The research community should focus instead on rejuvenation through therapies that repair and remove the cellular damage that causes aging, an approach that can actually meaningfully help the aged when realized. For all that rejuvenation is the obviously superior research strategy, however, it's taking time to convince the world of that truth. Time spent on trying to slow aging is little different in outcome to time spent investigating the details of aging but choosing to do nothing about it: a few years here and there, and nothing that is as effective as simple exercise and calorie restriction. There's no such thing as useless knowledge in the long term, but we already know enough to work effectively on human rejuvenation.

The new study quoted below will no doubt bolster the prospects of those groups presently raising funds for attempts to slow aging or further develop drug candidates derived from rapamycin. While looking at the results, however, you might compare them with plain old calorie restriction in mice, something that can produce twice the extension of healthy life shown here.

Mutant Mice Live Longer

MTOR is a kinase involved in myriad cellular processes, from autophagy to protein synthesis. Genetic studies of TOR in other organisms, such as yeast and flies, have implicated a role for the enzyme in lifespan. In mammals, however, mTOR is required for survival, making a knockout mouse model unfeasible. So the National Heart, Lung and Blood Institute's Toren Finkel and his colleagues decided to use a mouse in which transcription was only partially disrupted, reducing the levels of mTOR to about 25 percent of the normal amount.

All else being equal, the researchers found that normal mice typically lived 26 months, while those with less mTOR survived around 30 months. Finkel said the increase in lifespan was greater than other researchers have seen using the immunosuppressant rapamycin to inhibit mTOR. It's possible that having mTOR reduced beginning in the womb, rather than at middle age, could explain the disparity. Additionally, this new mutant affected the levels of both forms of mTOR - mTORC1 and mTORC2 complexes - rather than preferentially impacting one, as rapamycin would.

The paper on this research is open access, so head on over and take a look. I think you'll find it interesting. In particular note the author's cautions regarding the size of the life extension effect and the life span of the control mice in the discussion section: the number of mice used isn't large, and it's possible that the controls were just randomly a slightly short-lived group.

Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression

We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic (mTOR?/?) alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While mTOR?/? mice are smaller than wild-type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, mTOR?/? mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as mTOR?/? mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.

Source:
https://www.fightaging.org/archives/2013/08/decreased-mtor-expression-provides-20-mean-life-span-extension-in-mice.php

The immune system declines greatly with aging, and poor immune response is an important component of age-related frailty: old people become vulnerable to infections that the young can shrug off with ease. So we might expect to see that long-lived people have better immune systems, and that whatever underlying mechanisms cause that difference are to some degree inherited.

People may reach the upper limits of the human life span at least partly because they have maintained more appropriate immune function, avoiding changes to immunity termed "immunosenescence." Exceptionally long-lived people may be enriched for genes that contribute to their longevity, some of which may bear on immune function. Centenarian offspring would be expected to inherit some of these, which might be reflected in their resistance to immunosenescence, and contribute to their potential longevity. We have tested this hypothesis by comparing centenarian offspring with age-matched controls. We report differences in the numbers and proportions of both CD4+ and CD8+ early- and late-differentiated T cells, as well as potentially senescent CD8+ T cells, suggesting that the adaptive T-cell arm of the immune system is more "youthful" in centenarian offspring than controls. This might reflect a superior ability to mount effective responses against newly encountered antigens and thus contribute to better protection against infection and to greater longevity.

The goal of future medicine is to make inherited differences of this nature irrelevant. There are a number of promising approaches that may remove much of the age-related decline of immune function: regrow the atrophied thymus, where immune cells are cultured; create new immune cells in the clinic and infuse them regularly into older people; destroy the population of over-specialized memory cells that exist in the elderly, thus freeing up space for effective immune cells that can combat new threats.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23974207

Source:
https://www.fightaging.org/archives/2013/08/children-of-long-lived-parents-have-better-immune-systems.php

The 2045 Initiative is a fairly young but comparatively well-backed effort to generate more support for and technological progress towards non-biological means of human life extension: artificial bodies, and ultimately artificial brains, built to be far more resilient and maintainable than our present evolved equipment. There is some debate over whether this is an efficient course in comparison to medical research, but that end of the futurist community already primarily interested in strong artificial intelligence seem to like where this is going.

There is a lot of fascinating groundwork in reverse-engineering the human brain presently under way, and it's clear that neuroscience is going to become an interesting place to be over the next few decades. However, I remain unconvinced that any of this is going to help us get over the initial hurdles to extending human longevity, meaning the frailty and short life span of the human body and physical structures that support the mind, soon enough to matter. Artificial intelligence and human minds running on machinery will certainly come to pass, and I will be surprised if the latter fails to happen in the laboratory prior to 2050 given the pace at which available processing power is growing. However, and this is important, over that time scale most of us doing the writing and the reading here and now are dead without some means of medical treatment for aging. This is one of the reasons why I pay less attention to neuroscience and mind-machine interface development than I do to repair biotechnologies for the causes of aging.

The Global Futures 2045 conference series is a part of the 2045 Initiative advocacy, and the most recent event took place a couple of months ago. I noted some of the media reports at the time. A two part report published earlier this month is quoted below and focuses more on the presentations than did past articles in the popular press, which I think is a good thing.

The world according to Itskov: Futurists convene at GF2045 (Part 1)

The development of brain-computer interfaces (BCIs) to allow paralyzed individuals to control various external prosthetic devices, such as a remote robotic arm, was another key topic at GF2045. A very recent example of the BCI research Carmena and Maharbiz discussed is Neural Dust: An Ultrasonic, Low Power Solution for Chronic Brain-Machine Interfaces. The theoretical pre-print paper proposes neural dust - thousands of ultra-miniaturized, free-floating, independent sensor nodes that detect and report local extracellular electrophysiological data - with neural dust power and communication links established through a subcranial interrogator. With the purpose being to enable "massive scaling in the number of neural recordings from the brain while providing a path towards truly chronic BMI," the researchers' goal is "an implantable neural interface system that remains viable for a lifetime."

In Making Minds Morally: the Research Ethics of Brain Emulation, Dr. Anders Sandberg - a Computational Neuroscientist, and James Martin Research Fellow at the Future of Humanity Institute at Oxford University, and Research Associate at the Oxford Neuroethics Center - addressed the social and ethical impact of cognitive enhancement and whole brain emulation. "We want to get to the future," Sandberg said in his talk, "but that implies that the future had better be a good place. Otherwise, there wouldn't be a point in getting there - but that would mean in turn that the methods we're going to use to get to the future had better be good as well."

The world according to Itskov: Futurists convene at GF2045 (Part 2)

Dr. Theodore Berger gave the most groundbreaking presentation of the Congress - one that also received a standing ovation. In Engineering Memories: A Cognitive Neural Prosthesis for Restoring and Enhancing Memory Function, Berger discussed his extraordinary research in the development of biomimetic models of hippocampus to serve as neural prostheses for restoring and enhancing memory and other cognitive functions. Berger and his colleagues have successfully replaced the hippocampus - a component of the cortex found in humans and other vertebrates that transforms short-term memory into long-term memory - with a biomimetic VLSI (Very Large-Scale Integrated circuit) device programmed with the mathematical transformations performed by the biological hippocampus.

Dr. Randal Koene, neuroscientist, neuroengineer and science director of the 2045 Initiative, has been focusing on the functional reconstruction of neural tissue since 1994. In his Whole Brain Emulation: Reverse Engineering A Mind presentation and soon-to-be published book with the same title, Koene describes the process of progressing from our current condition to a possible substrate-independent mind achieved by whole brain emulation and cites a wide range of research, including the work of fellow GF2045 presenters.

Source:
https://www.fightaging.org/archives/2013/08/a-two-part-report-on-global-futures-2045.php

A conservative view of what lies ahead for Alzheimer's disease (AD) research sees incremental progress resulting from new and better investigative biotechnologies:

In the recently published work "The Biology of Alzheimer Disease" (2012), most of what is known about AD today is described in detail. The book culminates in a chapter called Alzheimer Disease in 2020, where the editors extol "the remarkable advances in unraveling the biological underpinnings of Alzheimer disease...during the last 25 years," and yet also recognize that "we have made only the smallest of dents in the development of truly disease modifying treatments." So what can we reasonably expect over the course of the next 7 years or so? Will we bang our heads against the wall of discovery, or will there be enormous breakthroughs in identification and treatment of AD?

Though a definitive diagnosis of AD is only possible upon postmortem histopathological examination of the brain, a thorough review of the book leads me to believe that the greatest progress currently being made is in developing assays to diagnose AD at earlier stages. It is now known that neuropathological changes associated with AD may begin decades before symptoms manifest. This, coupled with the uncertainty inherent in a clinical diagnosis of AD, has driven a search for diagnostic markers. Two particular approaches have shown the most promise: brain imaging and the identification of fluid biomarkers of AD.

The authors anticipate that advances in whole-genome and exome sequencing will lead to a better understanding of all of the genes that contribute to overall genetic risk of AD. Additionally, improved ability to sense and detect the proteins that aggregate in AD and to distinguish these different assembly forms and to correlate the various conformations with cellular, synaptic, and brain network dysfunction should be forthcoming in the next few years. Lastly, we will continue to improve our understanding of the cell biology of neurodegeneration as well as cell-cell interactions and inflammation, providing new insights into what is important and what is not in AD pathogenesis and how it differs across individuals, which will lead, in turn, to improved clinical trials and treatment strategies.

Link: http://www.alcor.org/magazine/2013/08/21/alzheimer-disease-in-2020/

Source:
https://www.fightaging.org/archives/2013/08/the-next-few-years-of-research-into-alzheimers-disease.php

A conservative view of what lies ahead for Alzheimer's disease (AD) research sees incremental progress resulting from new and better investigative biotechnologies:

In the recently published work "The Biology of Alzheimer Disease" (2012), most of what is known about AD today is described in detail. The book culminates in a chapter called Alzheimer Disease in 2020, where the editors extol "the remarkable advances in unraveling the biological underpinnings of Alzheimer disease...during the last 25 years," and yet also recognize that "we have made only the smallest of dents in the development of truly disease modifying treatments." So what can we reasonably expect over the course of the next 7 years or so? Will we bang our heads against the wall of discovery, or will there be enormous breakthroughs in identification and treatment of AD?

Though a definitive diagnosis of AD is only possible upon postmortem histopathological examination of the brain, a thorough review of the book leads me to believe that the greatest progress currently being made is in developing assays to diagnose AD at earlier stages. It is now known that neuropathological changes associated with AD may begin decades before symptoms manifest. This, coupled with the uncertainty inherent in a clinical diagnosis of AD, has driven a search for diagnostic markers. Two particular approaches have shown the most promise: brain imaging and the identification of fluid biomarkers of AD.

The authors anticipate that advances in whole-genome and exome sequencing will lead to a better understanding of all of the genes that contribute to overall genetic risk of AD. Additionally, improved ability to sense and detect the proteins that aggregate in AD and to distinguish these different assembly forms and to correlate the various conformations with cellular, synaptic, and brain network dysfunction should be forthcoming in the next few years. Lastly, we will continue to improve our understanding of the cell biology of neurodegeneration as well as cell-cell interactions and inflammation, providing new insights into what is important and what is not in AD pathogenesis and how it differs across individuals, which will lead, in turn, to improved clinical trials and treatment strategies.

Link: http://www.alcor.org/magazine/2013/08/21/alzheimer-disease-in-2020/

Source:
https://www.fightaging.org/archives/2013/08/the-next-few-years-of-research-into-alzheimers-disease.php