用数学模型还原人体衰老的动态过程,揭示晚年表观遗传变化加速现象。
Trajectory Inference of Human Aging from Cross-Sectional DNA Methylation Data

- 通过变分自编码器与最优传输结合,构建跨年龄的表观遗传轨迹推断框架。
- 在80年多组织数据上验证,发现晚年表观遗传波动显著加剧。
- 可生成个体化衰老路径,适合研究衰老机制或生物标志物开发。
DNA甲基化(DNAm)是生物衰老最可靠的分子标志之一。传统表观遗传时钟虽能准确预测日历年龄,但将衰老视为静态回归任务,仅输出单一评分,无法模拟全谱甲基化随时间连续演变。为此,本文将一生中的人类表观遗传衰老建模为从广泛可用的横断面数据中提取的离散年龄快照间的轨迹推断问题。提出两阶段计算流程:首先,采用年龄正则化的变分自编码器(VAE)将高维CpG谱映射到时序有序的潜在流形,并保留可逆解码器返回原始甲基化空间;其次,利用正则化非平衡最优传输(RUOT)建模该潜在空间中的连续演化,统一了确定性漂移、随机扩散与非守恒质量变化。通过DeepRUOT求解此鲁棒形式,模型无需强生物学先验即可自然适应群体密度变化如幸存者偏差与细胞流失。在大规模、覆盖80年跨度的多组织数据集上评估显示,模型具备强分布插值能力,并揭示出显著的晚年后代增长场,数学上捕捉了由随机表观遗传漂移驱动的方差扩张。最后,通过将连续潜在路径解码回单个CpG位点,重建并实证验证了不同的生物学衰老类型,提供了一种严谨且可生成的模拟人类分子衰老范式。
原文摘要 · Abstract (English)
DNA methylation (DNAm) serves as one of the most robust molecular biomarkers of biological aging. While conventional epigenetic clocks accurately predict chronological age from high-dimensional CpG profiles, they treat aging as a static regression task, meaning they can only output a single score rather than simulating how an entire profile continuously changes over time. To reconstruct these continuous dynamics, we frame lifelong human epigenetic aging as a trajectory inference problem across discrete age snapshots derived from widely available cross-sectional data. We introduce a two-stage computational pipeline: first, an age-regularized Variational Autoencoder (VAE) maps high-dimensional CpG profiles onto a chronologically ordered latent manifold while preserving a generative decoder bridge back to the original methylation space. Second, we model the continuous movement across this latent space via Regularized Unbalanced Optimal Transport (RUOT) that unifies deterministic drift, random diffusion, and non-conservative mass changes. By resolving this RUOT formulation using the DeepRUOT framework, our model fluidly accommodates population-level density shifts like survivorship bias and cellular attrition without requiring rigid biological priors. Evaluated on a large-scale, 80-year pan-tissue dataset, our model demonstrates robust distribution interpolation and uncovers a prominent late-life surge in the learned growth field that mathematically captures the variance expansion driven by stochastic epigenetic drift. Finally, by decoding continuous latent paths back to individual CpG sites, we reconstruct and empirically verify distinct biological aging archetypes, offering a rigorous, generative paradigm for simulating human molecular aging.
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