References About

I. Introduction

1.Abstract
2.Introduction

II. Fundamentals of Aging

1.Aging as a Time-Dependent Deleterious Consequence of Being Alive
2.Deleteriome: The Totality of Deleterious Change Associated with Life
3.Aging Is the Ancestral Default, whereas Nonaging Is a Derived State
4.Damage Increases in Open Systems
5.Life Is a Set of Self-Sustaining Processes that Locally Maintain Order
6.Life Persists Because Damage Can be Diluted, Repaired, Removed, or Buffered
7.Biological Age Is a Latent Measure of Position Along the Aging Trajectory
8.Organismal Aging Begins After the Point of Minimum Biological Age
9.Ground Zero Is the Developmental State of Minimum Biological Age
10.Development and Aging Proceed in Parallel Rather than Successively
11.Aging Is Not Programmed
12.Aging Is Both Stochastic and Directional
13.Aging Links Rising Damage Burden, Functional Decline, and Mortality Risk
14.Lifespan, Healthspan, and Longevity Are Related but Distinct Terms
15.Gompertzian Mortality Is Common but Not Universal
16.Species Longevity Is Set by Evolved Systems-Level Maintenance
17.Antagonistic Pleiotropy Shapes Lifespan Trade-Offs but Does Not Explain Aging’s Existence
18.Disposable Soma Captures Trade-Offs but Does Not Explain Aging’s Origin
19.There Are no Dedicated Aging Genes, Drivers, or Pathways
20.Aging Is Nearly Universal but Depends on Renewability and Damage Control
21.Naked Mole Rats Show that Aging and Mortality Acceleration Can be Uncoupled
22.Bowhead Whales Illustrate Systems-Level Solutions to Exceptional Longevity
23.Planaria and Hydra Show How Continual Renewal Can Support Negligible Senescence
24.Aging Increases Disease Vulnerability, and Disease Can be Viewed as Localized Accelerated Aging
25.Cancer Is an Age-Associated Disease with an Added Layer of Clonal Selection
26.Progerias Model Selected Aspects of Accelerated Aging, Not Aging in Full
27.Human Lifespan Has a Soft Limit
28.Aging Is Irreversible, but Biological Age Can Sometimes be Reduced or Reset
29.Rejuvenation Is a Measurable Reduction in Biological Age

III. Measuring Aging

1.Biomarkers of Aging Report Position on the Aging Trajectory
2.Aging Clocks Measure Projections of Biological Age Onto Specific Data Layers
3.Omics Clocks Are Practical Projections of Aging, Not Direct Measures of the Deleteriome
4.Biological Age Is Dynamic
5.Mortality, Morbidity, and Pace-of-Aging Clocks Capture Related but Distinct Aspects of Aging
6.Age Deviation Should be Interpreted Relative to the Reference Trajectory
7.Organ-, System-, and Subsystem-Specific Aging
8.Current Biomarkers of Aging Remain Limited in Accuracy, Coverage, and Causal Interpretability
9.Aging Biomarkers as Surrogate Endpoints
10.Large Health Models May Become Integrative Simulators of Aging

IV. Targeting Aging in Practice

1.Slowing Aging Means Durably Reducing the Rate of Deleteriome Increase
2.Large Lifespan Gains May be Easier to Obtain in Model Organisms than in Humans
3.Natural Species Longevity and Lab-Achieved Longevity Are Mechanistically Distinct
4.Caloric Restriction Can Slow Aging in a Context-Dependent Manner
5.Mean Lifespan Can be Increased by Targeting Weak Links and Reducing Fluctuations
6.Lifespan Plasticity Reflects System-Level Tuning of Damage, Maintenance, and Buffering
7.Lifespan Interventions Can Differ in Effect between Males and Females
8.Longevity Interventions Should be Personalized
9.Longevity Interventions Likely Matter Most Before Dominant Failures Are Established
10.Medical and Public Health Advances Have Already Extended Human Life Expectancy
11.Practical Lifespan Gains Today Come from Reducing Risk and Preserving Function
12.Strong Evidence for Slowed Aging in Humans Must Show Durable, Multilevel Benefit

V. Longer-Term Horizons

1.Radical Longevity Requires Addressing Conceptual Gaps and Pursuing New Intervention Strategies
2.Embryonic Rejuvenation May Offer Principles for Adult Rejuvenation
3.Partial Cellular Reprogramming May Rejuvenate, but Requires Control of Identity and Cancer Risk
4.Regeneration-Driven Rejuvenation
5.Heterochronic Parabiosis Suggests that Systemic Milieu Can Modulate Biological Age
6.Comparative Biology May Reveal Strategies for Radical Longevity
7.Replacement Is a Plausible Antiaging Strategy
8.Hybrid Strategies Could Extend Life by Externalizing and Replacing Bodily Functions
9.Brain-Machine Integration May Support Radical Longevity
10.Digital Immortality
11.Fully Stopping Human Aging Is Unlikely without Radically Transforming Biology
12.Progress Requires Better Measurements, Larger Datasets, and More Ambitious Interventions

VI. Conclusions and Outlook

1.Conclusions and Outlook

VII. Supplementary

1.What is time in aging?
2.Which disciplines converge to explain aging?
3.How random is the deleteriome?
4.Can future aging states be reliably predicted?
5.Is there a space of possible aging, and where do existing species sit within it?
6.Why does aging impose an arrow of time inside organisms?
7.Do bacteria age?
8.What are hallmarks of aging?
9.What is intrinsic capacity, and why does it matter for aging?
10.What is negligible senescence?
11.What does evolution select with regard to aging?
12.Does antigeria represent decelerated aging?
13.Why does life require rejuvenation across generations?
14.Is cellular senescence a cause of aging?
15.Is chronic inflammation a cause of aging?
16.Is oxidative damage a cause of aging?
17.Do telomeres drive aging?
18.Does mitochondrial dysfunction drive aging?
19.Are epigenetic changes causes of aging or readouts?
20.Is ‘aging begins at gastrulation’ literal?
21.What have we learned from aging of model organisms as applied to humans?
22.What is the relationship between programmed cell death and aging?
23.Why does lifespan often vary across sexes?
24.Is there evidence for adult age reversal in biomarkers?
25.Why do epigenetic clocks generalize so well?
26.What is systems aging?
27.What does validation mean for an aging biomarker?
28.What are longevity intervention types?
29.How do within-species lifespan interventions differ from cross-species longevity differences?
30.Why do many interventions have modest effects in mammals?
31.Why do interventions work across species?
32.Why can organ-specific strategies be more beneficial than universal interventions?
33.What is the evidence that aging is modifiable in mammals?
34.What are the conserved pathways that modulate aging?
35.What makes an intervention translationally credible for humans?
36.Can pharmacology slow aging?
37.Can an intervention extend lifespan without slowing the underlying rate of aging?
38.How does hormesis work and can it slow aging?
39.Can temperature modulation slow aging?
40.Where does sleep fit in aging biology?
41.Why does exercise help even though it is a stress?
42.Why do universal longevity interventions often involve tradeoffs?
43.What are realistic near-term goals in aging biology?
44.Can aging be stabilized?
45.If we rejuvenate an organ, would it change the biological age of the organism?
46.What are the main risks of rejuvenation therapies?
47.Why might combination therapies be necessary?
48.Are senolytics a form of rejuvenation?
49.What are major recent advances in the field?
50.Would progress come from individual labs or large, collaborative efforts?
51.How can aging research impact public health in the future?
52.Which funding or regulatory policy changes could speed up progress?
53.What can researchers do to ensure that aging science can be trusted?
54.What advice may be given to researchers entering the field now?
55.Where will the field be in the next 5 to 10 years?
56.Is cryonics a viable strategy for longevity?
57.Can damage dilution be engineered?
58.How should we implement slowing aging and rejuvenation?

V. Longer-Term Horizons

Rejuvenation, replacement, hybrid strategies, and what the field needs.

1.Radical Longevity Requires Addressing Conceptual Gaps and Pursuing New Intervention Strategies
2.Embryonic Rejuvenation May Offer Principles for Adult Rejuvenation
3.Partial Cellular Reprogramming May Rejuvenate, but Requires Control of Identity and Cancer Risk
4.Regeneration-Driven Rejuvenation
5.Heterochronic Parabiosis Suggests that Systemic Milieu Can Modulate Biological Age
6.Comparative Biology May Reveal Strategies for Radical Longevity
7.Replacement Is a Plausible Antiaging Strategy
8.Hybrid Strategies Could Extend Life by Externalizing and Replacing Bodily Functions
9.Brain-Machine Integration May Support Radical Longevity
10.Digital Immortality
11.Fully Stopping Human Aging Is Unlikely without Radically Transforming Biology
12.Progress Requires Better Measurements, Larger Datasets, and More Ambitious Interventions

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