A Fast Review of the Present Consensus on Mechanisms Determining Longevity
This densely written open access paper breezes through a sizable fraction of the the present consensus on the mechanisms driving aging. When reading through this sort of review, it is worth bearing in mind that different perspectives on the nature of aging may well categorize a given mechanism as either causative or a downstream consequence, or more important or less important in the progression of aging. That debate is more vital than it might at first seem. Making the wrong choice in a target mechanism for the development of therapies to treat aging will likely slow down progress by a couple of decades, as poor strategies are implemented and then found to have only modest beneficial effects, doing little to halt the progression of aging because they are intervening far downstream of the causes.
It is easy enough to say, well, try everything and the best approaches will win out in time. Yes, indeed, that will happen, but it will take quite the long time if, at the start, the wrong approaches are more dominant in the marketplace of ideas. We already have the past four or five decades as an example of just how long such a process can continue before better ideas start to make headway. Many of us don't have the luxury of waiting for the research and development communities to take the long way around.
Throughout history, humankind has been preoccupied with longevity, death, and immortality, as evidenced by the first known epic, describing Gilgamesh's futile quest for immortality. Death due to old age, however, appears to be rather rare in nature, as most species are confronted with various extrinsic sources of mortality, including predation, malnutrition, and life-threatening temperatures, all of which can limit the life span of individuals in their natural habitats. The vastly different life spans among closely related species were selected mainly via pressure exerted by extrinsic mortality risks that had to be balanced with the need for successful offspring generation. Some trees may persist thousands of years, whereas some insect species live for only a few days and other species, such as the small freshwater animal hydra, are thought to live indefinitely.
Over the past three decades, environmental and metabolic factors as well as evolutionarily conserved pathways that influence life span have been identified. Examples include several stress factors that, in excess, can negatively affect life span but that, in moderation, can trigger protective responses that lead to life span extension in a process called hormesis. For example, DNA damage is thought to accumulate in tissues during aging. DNA damage drives the aging process via mechanisms ranging from interference with replication and transcription to the DNA damage response (DDR) that triggers apoptosis and cellular senescence. A similar relationship can be observed regarding the nutritional state of animals, as severe nutrient and energy limitation can lead to death; however, calorie restriction (CR) or intermittent fasting has positive effects on life span in several model organisms, and modulation of metabolic parameters in a 2-year human trial showed potential benefits.
The immune system is an important regulator that not only profoundly influences life span directly by preventing premature death due to infections but also protects organisms via cancer surveillance and removal of senescent cells. While the prowess of the immune system fades during aging through a process called immunosenescence, nuclear DNA damage, accumulating extranuclear DNA, and senescent cells fuel inflammation. Targeting senescent cells has shown positive effects on immune function in mice and therefore appears to be a promising field of research to improve tissue aging in the elderly, including attempts to re-establish a balanced output of aging HSCs to regenerate lymphopoiesis during aging. In contrast, the senescence program might protect cells from transforming into cancer cells and has been implicated in tissue regeneration after skin injury. Together, these observations indicate that senescent cells serve dual roles in influencing life span: pro-longevity tumor suppression and tissue repair versus involvement in pro-aging inflammatory reactions.
What a fake this phrase is: "senescent cells [...] pro-longevity tumor suppression". Senescent cells are identical (except lack of dividing only and lack of telomerase expression) to cancer cells. When normal cell DNA gets damaged, the cell is speadily purged by immune system. When senescent cell DNA is damaged, the cell is already invisible and protected from immune system, and starts dividing fast as cancer. So the only role senescent cells have is anti-longevity TUMOR PROMOTION. The other role "wound healing" allegedly good is also a fake - the only role senescent cells have in wounds is scarring of the wound, which definitely is detrimental.
"Senescent cells are identical (except lack of dividing only and lack of telomerase expression) to cancer cells." no, they really are not.
"The other role "wound healing" allegedly good is also a fake" - nope, Campisi and others have already demonstrated the role of senescent cells in wound healing.
SilverSeeker, if you're interested in reading some of the research that Steve Hill has alluded to, here's a link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629/
Exactly how significant of a role senolytics will have in humans has yet to be seen, so while giving educated predictions is fine, it's important to keep dogma at bay and let the evidence and results do the talking. :)
Hi Quinn !
A week ago there was a piece here, yet another one of a long list published during several previous years on similar theme - how senescent cells avoid apoptosis.
https://www.fightaging.org/archives/2019/08/targeting-nkg2d-ligands-on-the-surface-of-persistent-senescent-cells-enables-their-destruction-by-the-immune-system/
These mechanisms are shared only by two classes of cells so far - cancer cells and senescent cells. Transformation form normal cell to cancer cell requires several changes to the single cell. They are too wide and dispersed to occur simultaneously often, regardless cancer is one of the most common illness. The path form normal cells to senescent cell to cancer cell requires they occur only one at a time, the first step happen on massive scale, and before DNA damage occur, the cell already posses properties which enable survival of the cancer cell from immune system. It's most likely hypothesis at the moment, as the simplest and having the greatest probability of occurence.
Hi Quinn, the article you link says "the senescence response". The senescence response means cycle arrest and marking the cell for disposal which the immune system does. Yet some cells survive this cleaning phase and turn into "lingering senescent cells". My criticism is that "anti cancer senescence response" cannot be extended nor equated as "anti cancer" to lingering senescent cells which are a failure of this anti-cancer mechanism. And these lingering senescent cells have all the mechanism that support cancer survival already in place, so they are only one single DNA damage away form cancer. And due to SASP they will acquire one anyway.
Good god is this article (https://f1000research.com/articles/8-1403/v1) hard to read and understand! Someone desperately needs to rewrite it in English. It would also help if the two ultra-educated authors (Robert Bayersdorf and Björn Schumacher from the University of Cologne in Germany) would cut to the chase and offer up more personal opinion and critical analysis on how to expand human lifespan, rather than being so carefully neutral.