Thursday, November 11, 2021

Aging—Knowing the Basics

Figure 1. The hallmarks of ageing (Source: [55])


The well-established nine hallmarks of aging include:[55]
  1. Genomic instability
  2. Shortening telomere length
  3. Epigenetic modifications
  4. Loss of proteostasis
  5. Deregulated nutrient sensing
  6. Mitochondrial dysfunction
    • SIRT3, an important stress-responsive deacetylase with cardio-protective and longevity enhancing properties involved in mitochondrial homeostasis, stem cells and tissue maintenance.[56,57]
  7. Cellular senescence
  8. Stem cell exhaustion
  9. Altered intracellular communication (Video 2)
have all been shown to be caused, at least in part, by sustained systemic inflammation.[45-54]

Video 1. Can ageing be delayed, stopped or even reversed? BBC News (YouTube link)

Inflammatory Clock (or iAge)


Inflammation plays a role in almost all chronic diseases of ageing including atherosclerosis, cancer, neurodegenerative diseases and diabetes.

From the blood immunome of 1,001 individuals aged 8–96 years, Sayed et al. developed a deep-learning method based on patterns of systemic age-related inflammation.[58] The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians.[58]
In centenarians, iAge was on average, 40 years lower than their corresponding chronological age. Note that the lower your iAge is, the better.

iAge is demonstrated to be correlated with multi-morbidity and immunosenescence and can be used as a ‘metric’ for immunological health. Based on the results of iAge research, here are the findings with increasing iAge ↑:
  • CXCL9 (an interferon-related chemokine) ↑
    • CXCL9 is the most robust contributor to iAge
    • Aging endothelial cells express high levels of CXCL9, which induces mRNA down-regulation of the cardio-protective SIRT3 — a gene known to be important in aging and endothelial cell function.
    • CXCL9 was validated as an indicator of cardiovascular pathology independent of age
    • One root cause of CXCL9 overproduction is cellular aging per-se, which triggers metabolic dysfunction with production of damage-associated molecular patterns (DAMPs).[62]
  • B cell and T cell immune responses ↓
    • A strong association with poor acute immune responses to cytokine stimuli was found, which is consistent with reports by two independent studies showing that high levels of baseline inflammatory markers correlate with weaker responses to hepatitis B and herpes zoster vaccine formulations.[59,60]
  • Potentiated monocyte responses ↑
  • JAK-STAT response ↓
    • Chronic inflammation is, at least in part, responsible for a reduced JAK-STAT response to cytokine stimulations in various leukocyte populations.[61]
This suggests that this immune ‘metric’ for human health versus disease may be useful as a companion diagnostic to inform physicians about patient’s inflammatory status, especially those with chronic diseases.
Their results indicate that CXCL9 and SIRT3 play an important role linking inflammation, cell metabolism, endothelial cell function and cardiovascular remodeling, which is consistent with prior work showing intricate interactions between inflammation and cell metabolism in tissue repair processes.[63]

Video 2. AGE Presents: Scott Leiser - Altered Cellular Communications (YouTube link)

Longevity Pathways


In Video 2 (must watch), Dr. Scott Leiser has shown that human may live longer by:
The common denominator of the above longevity pathways is stress—in the sense that either they are stresses directly or can turn on the stress response pathways indirectly (video 2 @7:52).  Note that under stress, organisms actually get healthier under low stress (hormetic effects). However, all of these longevity pathways also have some drawbacks or side effects in the real world (see Figure 3).

Figure 2.  Longevity pathway is conserved from yeast to humans (video 2 @6:30)

Figure 3.  Longevity pathways have drawbacks or side effects in the real world (video 2 @13:23)

Video 3. Living into your 90s (YouTube link)

Video 4.  Why We Age – And Why We Don't Have To (YouTube link)

Video 5.  Dr. David Sinclair: The Biology of Slowing & Reversing Aging  (YouTube link)

References

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    • This suggests that time-controlled activation of NRF2 may be critical for homeostasis in multicellular organism.
  66. A global clinical measure of fitness and frailty in elderly people
  67. DR. DAVID SINCLAIR: THE BIOLOGY OF SLOWING & REVERSING AGING
  68. New Insights into the Roles and Mechanisms of Spermidine in Aging and Age-Related Diseases
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