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.