You raise good points --all of them – @CronosTempi. The differences in our views spring mostly from where we find ourselves on the spectrum of this artificial dichotomy.
Viewpoint 1: Geroscience Hypothesis — Aging as a Primary, Targetable Driver of Disease
This is arguably the dominant paradigm in modern aging research and has substantial theoretical and empirical support. Its core tenet posits that there is a set of core biological processes that drive aging itself. These processes are the primary risk factor for nearly all major chronic diseases, including cancer, neurodegeneration, and, of course, atherosclerotic cardiovascular disease (ASCVD). By targeting these core processes, we can simultaneously delay or prevent a wide spectrum of age-related diseases and extend healthspan.
The currently recognized hallmarks include:
- Genomic instability
- Telomere attrition
- Epigenetic alterations
- Loss of proteostasis
- Disabled macroautophagy
- Deregulated nutrient-sensing
- Mitochondrial dysfunction
- Cellular senescence
- Stem cell exhaustion
- Altered intercellular communication
- Chronic inflammation (Inflammaging)
- Dysbiosis
Taking Apo(b) as a discussion point. Apo(b)-containing lipoproteins are not just a risk factor for a plumbing problem in the arteries. They are a direct driver of at least two hallmarks: deregulated nutrient-sensing (lipids are key signaling molecules) and chronic inflammation. The deposition of LDL particles in the arterial wall incites an inflammatory response that is a classic example of localized inflammaging, which can then become systemic. Therefore, lowering Apo(b) is not merely disease prevention; it is a geroprotective intervention that targets a core hallmark.
Viewpoint 2: Network Failure Hypothesis — Aging as an Emergent Property of Decline Within and Between Interconnected Systems
This view does not contradict the Geroscience Hypothesis but rather reframes it. It is less about a single “program” of aging and more about the emergent property of a complex, interconnected system losing its resilience. The core tenant here is seeing the organism as a robust network of interacting physiological systems optimized for function in early life. Aging is the progressive and accelerating failure of this network. The “hallmarks” (or specific hallmarks) are not independent phenomena but are deeply intertwined nodes in this network. A decline in one area (e.g., mitochondrial function) places stress on others (e.g., increases genomic instability, triggers senescence), leading to a cascading collapse that manifests as what we call “aging.” My view on this is that the hallmarks in Viewpoint 1 are not siloed.
Interdependence of Hallmarks
- Genomic instability can directly trigger cellular senescence.
- Mitochondrial dysfunction leads to the production of reactive oxygen species (ROS) that can cause genomic instability.
- Senescent cells secrete a cocktail of inflammatory proteins (the SASP), which drives inflammaging and alters intercellular communication.
Antagonistic Pleiotropy
While theory, there is a strong foundation for the network view. It posits that genes that are beneficial for development and reproduction in youth can have unselected, detrimental effects later in life. A prime example is the growth hormone/IGF-1/mTOR axis, which is critical for reaching maturity but whose continued high activity in later life accelerates aging by driving several hallmarks. This suggests aging is a byproduct of a system optimized for early, not late, life.
Resilience as a Biomarker
Researchers are increasingly focused on measuring the body’s ability to recover from a stressor (e.g., illness, injury) as a key indicator of biological age. This dynamic network resilience may be a more accurate measure of aging than any static biomarker.
The network failure view would frame the role of Apo(b) perfectly. Elevated Apo(b) is a significant perturbation to the network. Locally, it It destabilizes the vascular endothelial sub-network, leading to ASCVD. Systemically the chronic inflammatory response it triggers (inflammaging) is a massive stressor on the entire network. This systemic inflammation can exhaust the immune system, promote senescence in distant tissues, and contribute to insulin resistance. Thus, lowering Apo(b) does more than fix a local problem; it reduces a major source of systemic noise and stress, thereby increasing the resilience and stability of the entire physiological network. It calms a key inflammatory node, allowing the rest of the system to function better.
Is There a Best Way to Look at This Issue?
The most accurate and useful perspective is a synthesis of these two views. This avoids a false dichotomy and embraces the complexity of the biology. Aging is the progressive failure of a complex physiological network (Viewpoint 2), and the “Hallmarks of Aging” represent the most critical, interconnected nodes whose individual failures drive the overall system collapse (Viewpoint 1).
Therefore, an intervention can be, and often is, both. It is a disease-specific intervention because its most visible and measurable effect is on a particular pathophysiology (e.g., lowering Apo(b) reduces plaque formation). It is a geroprotective intervention because the node it targets (e.g., lipid-driven inflammation) is so deeply integrated into the larger network of aging that stabilizing it has beneficial, pleiotropic effects that enhance the resilience of the whole system. But it is also a powerful intervention against the process of aging by mitigating chronic inflammation, a core hallmark and a driver of network-wide instability. The distinction, while useful for regulatory and clinical purposes, is ultimately artificial from a biological standpoint.
. There is abundant evidence that cold temperatures extend the lifespans of animals in those environments. I don’t want to get into it here, because it’s a whole other universe of data… that’s one of the biggest losses in the demise of the CR Society website - there was a ton of research gathered on CE in one place. A unique resource.
If you have any papers on how cold environments affect longevity that you think are important please share. Obviously reaction rates generally increase with temperature, so I certainly find it plausible that extrinsically lowered body temp can lower “effective” temperature.
. I’m focused on researching other things and don’t want to go back to digging up all that stuff… my apologies, the limitations of time and concentration in this 67 yo:nerd_face:.
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