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Why Do We Age? The Integrated Aging Theory Framework

The Integrated Aging Theory Framework provides a comprehensive theoretical framework for understanding aging across organismal, organ, tissue, cellular, and molecular levels.

ORIGINAL ARTICLE

Huang, Bilu. Why Do We Age? The Integrated Aging Theory Framework. SSRN Preprint, 2026.

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Overview

When killifish species with different lifespans that evolved under distinct rainy-season lengths are raised together in the same aquarium, their lifespan differences persist, providing evidence that aging after sexual maturation is still genetically programmed.

Organismal aging is driven by replicative senescence of adult stem cells. Our work shows that cellular senescence is co-regulated by telomeres and ribosomal DNA (rDNA) through the p53 pathway. Moreover, the 11 established hallmarks of aging are also downstream consequences mediated by telomere and/or rDNA shortening through the p53 pathway.

The Integrated Aging Theory Framework consists of four major components:

1. The Essence of Aging: Aging Is Fundamentally a Genetic Program. Key publication: Programmed Aging Theory Defeats Damage Accumulation Theory of Aging

2. Adult Stem Cell Theory of Organismal Aging. Foundational publication: The Mechanism, Significance and Treatment of Aging 1998 · In Chinese

3. TRCS Model of Cellular Senescence. Key publication: Telomere DNA and Ribosomal DNA Co-regulation Model for Cell Senescence 2021 · In Chinese

4. Causality of Aging Hallmarks. Key publication: Causality of Aging Hallmarks

01

The Essence of Aging

The theories of aging are broadly divided into two categories: the damage accumulation (entropy increase) theory and programmed aging theory.

Over billions of years of evolution, organisms have evolved mechanisms to counteract diverse forms of random molecular damage. In addition, all living organisms follow relatively fixed timelines of development, maturation, aging, and death. Furthermore, differential gene expression occurs during replicative cellular senescence. Collectively, these observations indicate that the essence of aging is a genetic program.

Furthermore, three strains of killifish originating from regions with distinct rainy seasons, with lifespans of 3 months, 9 months, and 16 months, respectively, were raised in the same aquatic environment. Their lifespan differences persisted under identical rearing conditions.

This further indicates that aging after sexual maturation remains under programmed regulation. The accumulation of random molecular damage cannot explain why these three congeneric killifish strains, which have highly similar body structures, exhibit such large lifespan differences that precisely correspond to the lengths of rainy seasons in their native habitats.

Scientific illustration of the silkworm life cycle from eggs and larva to cocoon, adult moth, reproduction, senescence, and death.
Figure 1. The life cycle illustrates the programmed temporal sequence of development, maturation, reproduction, senescence, and death. © Xiaowen Hu
Diagram showing adult stem cells producing functional cells through life, with progressive changes associated with aging.
Figure 2. Each time adult stem cells divide, the daughter cells become more senescent than the previous generation. Functional cells differentiated from senescent adult stem cells are also senescent, leading to the progressive aging of tissues, organs, systems, and the organism. © Bilu Huang

02

Adult Stem Cell Theory of Organismal Aging

The tissue cells that make up an organism fall into two broad categories: terminally differentiated cells and rare adult stem cells. Both cell types can be eliminated by the immune system due to cellular senescence, gene mutation, viral infection and other stressors, followed by tissue renewal via self-renewal and differentiation of adult stem cells.

However, adult stem cells possess a limited replicative capacity; with each division, the resulting daughter cells are physiologically older than their parent cells, a phenomenon termed "replicative senescence".

Accordingly, the root cause of organismal aging ultimately lies in the replicative senescence of adult stem cells.

03

TRCS Model

If aging is regulated by a genetic program, there must exist a countdown element (biological countdown timer) to drive the progression of this program. The theory of replicative cellular senescence posits that telomeres serve as the countdown element governing the replicative capacity of cells.

However, telomere shortening does not occur in certain species or distinct cell types within the same species, yet their cells still possess a limited replicative lifespan. Even when telomerase is used to maintain elongated telomeres, cell proliferation eventually ceases. Accordingly, there must be another countdown element in the cell nucleus besides telomeres. On this basis, I proposed the "Telomere DNA and Ribosomal DNA Co-regulation Model for Cellular Senescence (TRCS)."

Within the TRCS model, multi-copy tandemly repeated telomere DNA and ribosomal DNA (rDNA) serve as the countdown elements of the timer, analogous to sand grains in an hourglass. Accordingly, the TRCS model postulates that progressive shortening of telomere arrays and/or rDNA arrays generates a temporal concentration gradient of the tumor suppressor protein p53 along the timeline.

Since p53 binds to the promoters and enhancers of numerous genes, the synthesis rates of ATP and proteins continuously decline over time. Meanwhile, certain genes are specifically upregulated, while others are specifically downregulated. Transcriptomic profiling of mouse tumor cells has identified more than 5,000 p53-associated differentially expressed genes; aged hematopoietic stem cells exhibit upregulation and downregulation of 1,500 genes. These transcriptional changes drive programmed gene expression, gradually transitioning cells from a youthful state to a senescent state.

TRCS model comparing a young cell and a senescent cell with telomere, rDNA, and p53 changes.
Figure 3. The Telomere DNA and ribosomal DNA Co-regulation Model for Cell Senescence (TRCS Model). © Bilu Huang & Xiaowen Hu
Scientific diagram with p53 at the center connecting to multiple downstream aging hallmark nodes.
Figure 4. The eleven major hallmarks of aging mediated by telomeres and rDNA through the p53 pathway. © Bilu Huang & Xiaowen Hu

04

Causality of Aging Hallmarks

Interpreting the aging mechanism based on the TRCS model, countdown elements (analogous to sand in an hourglass) function as upstream drivers of cellular senescence. p53 acts as a mediator between upstream and downstream processes.

The various phenotypes associated with cellular senescence represent downstream events induced by countdown elements through p53 signaling.

Factors that influence the rate of aging affect cellular and organismal aging by regulating the consumption rate of countdown elements.

Author Bilu Huang
License CC BY-NC-ND 4.0

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