Measuring Biological Aging in Humans: A Quest

Presented by: Tara Mei

Discussion Summary

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Paper(s): Ferrucci, L., Gonzalez-Freire, M., Fabbri, E., Simonsick, E., Tanaka, T., Moore, Z., Salimi, S., Sierra, F., de Cabo, R, Measuring biological aging in humans: A quest. Aging Cell 19:e13080 (2020).

Resilience

“The harmonic assemblage of the biochemical processes that are aimed at maintaining the identity, integrity, and autonomy of individual organisms against the perturbations induced by both internal and external environments”

= A bunch of things keeps us intact when shit happens

Prenatal stages/birth/childhood

Changes are fast + massive + predetermined + stereotyped

Adulthood

Stability

…thanks to compensatory and homeostatic mechanisms

Old age

Mechanisms fade, damage accumulates

Resilience mechanisms

Accumulated damage

Which?

Damage only emerges when compensatory mechanisms are exhausted

Normal

Accelerated

Accelerated

“Developing an index of biological aging is perhaps the most critical milestone required to advance the field of aging research.”

1. Test the geroscience hypothesis:

“Does biological aging cause global susceptibility to disease when human get old?”

2. Transform preventative care

3. Identify genetic, environmental, behavioural risk factors

4. Refine therapeutic choices

Why develop biomarkers for aging?

1. Genomic instability

2. Telomere length

3. Cellular senescence

4. Epigenetics

5. Mitochondrial function

6. Proteostasis

7. Stem cell exhaustion + deregulated nutrient sensing + altered intercellular communication

Current aging biology measures

Evidence

Lacking

• Somatic mutations accumulate

1. Genomic Instability

Measurement

Unsatisfactory

• Assays not independently verified, not applied to large populations, address only a subset
• No gold standard assay

Evidence

Lacking

• Telomere length does shorten with age
• Telomere shortening linked to some bad outcomes

2. Telomere length

Measurement

Unsatisfactory

• Noise: stuff exists but results inconsistent
• Looking for a gold standard assay

Evidence

Conditional?

• SCs accumulate (depending)
• Senescence is very heterogeneous
• No unique biomarker

3. Cellular senescence

Measurement

Complicated

• Lots of efforts underway

Evidence

Promising

• Clocks have been strongly predictive of mortality and adverse outcomes e.g. dementia
• 5hmC associated with AD and general brain aging

4. Epigenetics

Measurement

Possible

• Measurable in blood via a few methods
• Stable over time

Evidence

Promising

• Several methods show decline in oxidative phosphorylation with age in several tissues
• Reduced mitochondrial function associated with reduced mobility

5. Mitochondrial function

Measurement

Several measures, none fully satisfactory:

P31 MRS

Muscle biopsies

ROS assays

mtDNA copy number

• Possibly super useful, but need careful standardization

Evidence

Promising

• Genetic variants in autophagy genes contribute to disease
• Autophagy becomes defective with aging
• Compounds that modulate autophagy have anti-aging properties

6. Proteostasis

Measurement

Complicated

• Static measures are unreliable
• Measures that track the dynamic flux of autophagy are better
• Adequately quantifying autophagy requires multiple measures

Evidence

Lacking

• None sufficiently characterised

7. Stem cell exhaustion, deregulated nutrient sensing, altered intercellular communication

Measurement

Lacking

• Only a few types of stem cells easily accessible
• No data on how stem cells change with age

1. Genomic instability

2. Telomere length

3. Cellular senescence

4. Epigenetics

5. Mitochondrial function

6. Proteostasis

7. Stem cell exhaustion + deregulated nutrient sensing + altered intercellular communication

Current aging biology measures

Red: Not promising

Orange: Somewhat promising

Green: Promising

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(based on currently available evidence + measurement technology)

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1. Genomic instability

2. Telomere length

3. Cellular senescence

4. Epigenetics

5. Mitochondrial function

6. Proteostasis

7. Stem cell exhaustion + deregulated nutrient sensing + altered intercellular communication

Are these measures multifaceted expressions of the same core process, or have they evolved independently?

What’s upstream and downstream?