Why Aging May Be a Program, Not a Breakdown

Junyue Cao, a cell biologist at Rockefeller University in New York City, analyzed gene expression in millions of mouse cells from different life stages.

纽约市洛克菲勒大学的细胞生物学家曹俊跃分析了数百万个不同生命阶段小鼠细胞的基因表达。

He was surprised to find that “changes in aging are not universal across all the cells,” he said.

他惊讶地发现“衰老的变化并不是所有细胞都普遍存在的，”他说。

In some ways, we know aging when we see it, from the graying of hair to the wrinkling of skin to declines in motor, sensory, and cognitive capacities.

在某些方面，我们一看到衰老就知道了，从头发变白到皮肤起皱，再到运动、感觉和认知能力的下降。

Yet the underlying biology of aging remains a matter of uncertainty and debate.

然而，衰老的基本生物学仍然是一个不确定性和争论的问题。

Many lines of research align with the theory that aging is a direct result of decay — the inevitable degradation of molecules (including proteins or DNA), organelles, cells, or whole organs — from external assault or inexorable breakdown.

许多研究都遵循这样的理论：衰老是腐烂的直接结果，腐烂是分子（包括蛋白质或 DNA）、细胞器、细胞或整个器官不可避免的降解，是由于外部攻击或不可阻挡的崩溃而导致的。

When the body’s repair mechanisms fail to keep pace with these changes, like a factory with deteriorating equipment and too few mechanics, it manifests as the known signs of aging and, eventually, death.

当身体的修复机制无法跟上这些变化时，就像一家工厂的设备日益老化且技工太少，就会表现为已知的衰老迹象，并最终导致死亡。

The idea makes a lot of sense, but according to the cell biologist Junyue Cao , it’s inaccurate.

这个想法很有道理，但根据细胞生物学家曹俊跃的说法，这是不准确的。

Far from a random but linear process of wear and tear, he argues, aging is a stepwise, programmed, orderly affair.

他认为，衰老并不是一个随机的、线性的磨损过程，而是一个逐步的、有计划的、有序的过程。

“The destruction of the system is programmed at a very early stage,” said Cao, who heads the Laboratory of Single-Cell Genomics and Population Dynamics at Rockefeller University.

洛克菲勒大学单细胞基因组学和群体动力学实验室负责人曹说：“系统的破坏是在很早的阶段就计划好的。”

Using technology that offers a systemwide view of the aging process in mice, Cao has outlined discrete stages of aging, akin to those of embryonic development, that are defined by changes in molecular signals and specific cell populations.

曹利用提供小鼠衰老过程全系统视图的技术，概述了衰老的离散阶段，类似于胚胎发育阶段，这些阶段是由分子信号和特定细胞群的变化定义的。

In humans, the process likely begins before age 30.

对于人类来说，这个过程可能在 30 岁之前就开始了。

Cao’s interest in aging began in high school in Hebei, China, when he became acutely aware that his grandparents and parents were not going to live forever.

曹对衰老的兴趣始于中国河北的高中，当时他敏锐地意识到他的祖父母和父母不会永远活下去。

While many teenagers awakening to mortality might turn to poetry or self-destructive behavior, Cao turned to science.

许多意识到死亡的青少年可能会转向诗歌或自我毁灭行为，但曹转向了科学。

Finding a way to slow aging became his lifelong goal, and it’s why he chose biology as his major at Peking University in Beijing.

寻找延缓衰老的方法成为他一生的目标，这也是他选择北京大学生物学专业的原因。

Initially, Cao assumed that the deterioration of particular proteins and protein networks was responsible for aging, in line with the prevailing model.

最初，曹认为特定蛋白质和蛋白质网络的退化是导致衰老的原因，这与流行的模型一致。

But then after college, when he was working in a lab trying to identify those proteins, he realized that a daunting number of them were associated with aging, and that their effects depended on the type of cell in which they were operating.

但大学毕业后，当他在实验室工作试图识别这些蛋白质时，他意识到其中数量惊人的蛋白质与衰老有关，而且它们的影响取决于它们所在的细胞类型。

It was a picture both more complex and more organized than he had thought.

这幅图画比他想象的更复杂、更有条理。

Cao decided he needed data — lots of it — on thousands of molecular changes across hundreds of cell types.

曹认为他需要大量数据，涉及数百种细胞类型的数千种分子变化。

As a graduate student, he developed a high-throughput technology that could quantify these dynamics in embryonic development.

作为一名研究生，他开发了一种高通量技术，可以量化胚胎发育中的这些动态。

When he started his own lab at Rockefeller in 2020, he put this technology to work on aging.

2020 年，当他在洛克菲勒开设自己的实验室时，他将这项技术应用于衰老研究。

In graduate school, Cao developed tools to identify changes in gene expression during embryonic development in mice.

在研究生院，曹开发了一些工具来识别小鼠胚胎发育过程中基因表达的变化。

Now his lab applies these tools across an animal’s entire lifespan.

现在，他的实验室将这些工具应用于动物的整个生命周期。

In one series of experiments, Cao and his team processed 21 million cells, sampled from 14 tissues or organs in about 50 male and female mice at five life stages, and built a data set of gene expression for each cell.

在一系列实验中，曹和他的团队处理了 2100 万个细胞，从大约 50 只雄性和雌性小鼠五个生命阶段的 14 个组织或器官中取样，并为每个细胞建立了基因表达数据集。

“It’s extremely large-scale data,” Cao said.

“这是非常大规模的数据，”曹说。

“You know which organ it’s from and which age it’s from, and you also know extensive molecular information.” Each stage was marked by a dramatic decline in or expansion of specific cell types.

“你知道它来自哪个器官、来自哪个时代，而且你还知道广泛的分子信息。”每个阶段都以特定细胞类型的急剧下降或扩张为标志。

Two of his landmark papers, published in 2025 and 2026 in Science, point to a radical redistribution of the cells that make up the body as mammals age, and describe some of the epigenomic instructions that guide this process.

他于 2025 年和 2026 年在《科学》杂志上发表的两篇具有里程碑意义的论文指出，随着哺乳动物年龄的增长，构成身体的细胞会发生彻底的重新分配，并描述了指导这一过程的一些表观基因组指令。

“There are molecular changes and maybe some other changes in aging,” Cao said, “but they all converge in the remodeling of the cell society.”

曹说：“衰老过程中存在分子变化，也许还有其他一些变化，但它们都集中在细胞社会的重塑中。”

Quanta spoke with Cao about evidence for the programmed theory of aging, what happens at each stage, and why aging mammals are like trees shedding leaves.

广达与曹谈论了程序化衰老理论的证据、每个阶段会发生什么，以及为什么衰老的哺乳动物就像树木落叶一样。

The interview has been condensed and edited for clarity.

为了清晰起见，采访内容已经过精简和编辑。

Back in college, I thought the problem of aging that needed solving was the lack of a drug.

回到大学时，我认为需要解决的衰老问题是缺乏药物。

I thought that we were going to develop some magic drug or chemical that we could use to increase the lifespan of animals.

我以为我们要开发一些神奇的药物或化学物质，可以用来延长动物的寿命。

So I joined a lab working on computational drug design, trying to design peptides that target molecules related to aging.

因此，我加入了一个从事计算药物设计的实验室，试图设计针对与衰老相关的分子的肽。

But the major challenge was that we didn’t know what molecules to target.

但主要的挑战是我们不知道要针对哪些分子。

Cao’s analysis required enormous volumes of data: tens of thousands of gene expression changes across 21 million cells, sampled from 14 tissues or organs in about 50 male and female mice at five life stages.

曹的分析需要大量数据：从约 50 只雄性和雌性小鼠五个生命阶段的 14 个组织或器官中采集的 2100 万个细胞中数以万计的基因表达变化。

After I graduated, I moved to the U.S. and worked at the Jackson Laboratory [a Maine-based biomedical research nonprofit] as a research assistant studying molecular pathways associated with aging in mice.

毕业后，我搬到了美国，在杰克逊实验室（一家位于缅因州的生物医学研究非营利组织）担任研究助理，研究与小鼠衰老相关的分子途径。

I thought that by studying pathways, we could identify a [drug] target and, from there, develop drugs to increase lifespan.

我认为通过研究途径，我们可以确定[药物]靶点，并从那里开发药物来延长寿命。

But after a few years, I learned that aging cannot be explained by a single pathway or target.

但几年后，我了解到衰老不能用单一途径或目标来解释。

It involves many different pathways, and these pathways have very different effects on different cell types in the body.

它涉及许多不同的途径，这些途径对体内不同的细胞类型有非常不同的影响。

I wanted to understand how aging progresses on a molecular level across hundreds to thousands of cell types in different organs.

我想了解不同器官中成百上千种细胞类型在分子水平上的衰老过程。

A major challenge is that aging involves changes across many different levels — molecules, organelles, cells, organs, and the whole body.

一个主要挑战是衰老涉及许多不同层面的变化——分子、细胞器、细胞、器官和整个身体。

To measure changes at all these levels, we needed technology that was both high throughput, which means you can use it to scan not just one cell or cell type but millions of cells across an entire organism, and high resolution, so you can see very detailed changes at the cellular and molecular levels.

为了测量所有这些水平的变化，我们需要高通量和高分辨率的技术，这意味着您不仅可以使用它扫描一种细胞或细胞类型，还可以扫描整个生物体中的数百万个细胞，这样您就可以在细胞和分子水平上看到非常详细的变化。

I applied to graduate school, where I developed tools that could scan the entire mammalian organism, from the brain to the kidneys to the lungs, while detailing tens of thousands of gene expression changes within single cells across hundreds of different cell types.

我申请了研究生院，在那里我开发了可以扫描整个哺乳动物有机体（从大脑到肾脏到肺部）的工具，同时详细说明了数百种不同细胞类型的单个细胞内数以万计的基因表达变化。

When I got to Rockefeller, we used this technology to understand the dynamics of the whole system in aging.

当我到达洛克菲勒时，我们使用这项技术来了解整个系统老化的动态。

During distinct time windows as an animal ages, different cell types undergo distinct dynamics, according to Cao’s lab’s experiments.

根据曹实验室的实验，在动物衰老的不同时间窗口内，不同的细胞类型经历不同的动态。

Some expand, some decline, and others remain stable.

有些扩张，有些下降，有些则保持稳定。

In one set of studies, we extracted more than 20 million cells from various organs from mice of different ages: 3, 6, 12, 16, and 23 months — roughly equivalent to 20, 30, 50, 60, and 75 years in humans.

在一组研究中，我们从不同年龄的小鼠的各个器官中提取了超过 2000 万个细胞：3、6、12、16 和 23 个月，大致相当于人类的 20、30、50、60 和 75 岁。

We analyzed the expression of 20,000 genes per cell and used this information to define the cell types.

我们分析了每个细胞 20,000 个基因的表达，并使用这些信息来定义细胞类型。

Then we tracked their population dynamics.

然后我们跟踪了它们的种群动态。

We found that not every cell type gets changed in aging.

我们发现并非所有细胞类型都会在衰老过程中发生变化。

We identified 536 main cell types and 1,828 subtypes.

我们鉴定了 536 种主要细胞类型和 1,828 种亚型。

Only about one-quarter of these subtypes show a strong shift in aging.

这些亚型中只有大约四分之一表现出明显的衰老变化。

Others remain stable across the lifespan.

其他人在整个生命周期中保持稳定。

It is surprising to find that changes in aging are not universal across all the cells, that there are specific cell populations that are more vulnerable.

令人惊讶的是，衰老的变化并不是所有细胞都普遍存在的，有些特定的细胞群更容易受到伤害。

We found that aging can be separated into distinct time windows.

我们发现衰老可以分为不同的时间窗口。

In each window, specific groups of cells show coordinated dynamics.

在每个窗口中，特定的细胞群显示出协调的动态。

In the early phase, for example, we see that some cell types are rapidly depleted.

例如，在早期阶段，我们看到某些细胞类型迅速耗尽。

This is followed by another phase, in which other cells are greatly expanded.

接下来是另一个阶段，其中其他细胞大大扩展。

In the first stage, 3 to 6 months in a mouse [about 20 to 30 years in a human], there is a loss of certain fat and muscle cells, and of two immature cell types in the brain that have the capacity to regenerate different types of brain tissue.

在第一阶段，小鼠的 3 至 6 个月（人类的大约 20 至 30 年）会损失某些脂肪和肌肉细胞，以及大脑中具有再生不同类型脑组织能力的两种未成熟细胞类型。

“Our claim is that aging is not so much molecular damage as a remodeling of the entire cell society,” Cao said.

“我们的主张是，衰老与其说是分子损伤，不如说是整个细胞社会的重塑，”曹说。

Between 6 and 12 months in a mouse [equivalent to a person in their 30s and 40s], we see dramatic depletion of cells needed to maintain the body’s tissues.

在小鼠（相当于 30 多岁和 40 多岁的人）的 6 到 12 个月期间，我们发现维持身体组织所需的细胞急剧减少。

These include tenocytes [the primary component of tendons]; the cells that wrap around blood vessels and stabilize the circulatory system; the smooth muscle cells of the colon; and kidney epithelial cells, which filter toxins from the blood.

其中包括肌腱细胞[肌腱的主要成分]；包裹血管并稳定循环系统的细胞；结肠平滑肌细胞；和肾上皮细胞，过滤血液中的毒素。

Also in decline are some immune cells that protect specific tissues such as the intestine.

一些保护肠道等特定组织的免疫细胞也在减少。

At around 12 months in mice [roughly 40 to 50 years in humans], there is a shift from cell depletion to cell expansion.

小鼠大约 12 个月（人类大约 40 到 50 岁）时，细胞会从细胞耗竭转变为细胞扩张。

The first expansion wave is dominated by immune cells, but also includes select cells in the lungs, kidneys, and other organs whose properties have changed as a result of stress or inflammation.

第一波扩张以免疫细胞为主，但也包括肺、肾和其他器官中的特定细胞，这些细胞的特性因压力或炎症而发生了变化。

At around 16 months in mice [late 50s and beyond in humans], specialized aging-associated immune cells expand.

小鼠大约 16 个月大时（人类则为 50 多岁及以上），与衰老相关的专门免疫细胞会扩张。

When these selfish, uncontrolled cells emerge, they will eventually proliferate and destroy the system.

当这些自私、不受控制的细胞出现时，它们最终会增殖并破坏系统。

In the meantime, they may contribute to the increased risk with age of inflammatory conditions such as heart disease, arthritis, cancer, and chronic respiratory illnesses.

与此同时，随着年龄的增长，它们可能会增加患心脏病、关节炎、癌症和慢性呼吸道疾病等炎症性疾病的风险。

Yes, researchers have observed a phenomenon called “abrupt aging” in middle-aged humans that is consistent with the cell population dynamics we saw.

是的，研究人员在中年人类中观察到一种称为“突然衰老”的现象，这与我们看到的细胞群动态一致。

When researchers analyze protein signatures in human blood, they see a significant change between the mid-40s and late 50s.

当研究人员分析人类血液中的蛋白质特征时，他们发现 40 多岁到 50 多岁之间存在显着变化。

People also tend to report an abrupt decline in function in middle age, which is also when there is a rise in susceptibility to age-related diseases such as cancer and some neurodegenerative diseases.

人们还倾向于报告在中年时身体机能突然下降，这也是与年龄相关的疾病（例如癌症和一些神经退行性疾病）的易感性上升的时期。

Previously, people saw aging as a linear accumulation of damage to molecules such as proteins and DNA.

此前，人们将衰老视为蛋白质和DNA等分子损伤的线性累积。

But we found that aging is not a linear process.

但我们发现衰老并不是一个线性过程。

It’s more like a developmental process, in which there are distinct stages that involve coordinated changes in specific cell types across different organs.

它更像是一个发育过程，其中存在不同的阶段，涉及不同器官中特定细胞类型的协调变化。

Our claim is that aging is not so much molecular damage as a remodeling of the entire cell society.

我们认为，衰老与其说是分子损伤，不如说是整个细胞社会的重塑。

Cao’s research suggests that in humans the aging program begins before age 30.

曹的研究表明，人类的衰老过程在 30 岁之前就开始了。

Our technology allows us to examine the genomic program that governs the function of each cell — which regions of the genome are active and which are silent.

我们的技术使我们能够检查控制每个细胞功能的基因组程序——基因组的哪些区域是活跃的，哪些区域是沉默的。

If it’s random molecular damage, we might see random changes across the genome.

如果是随机分子损伤，我们可能会看到整个基因组的随机变化。

But we always see the same regions that are open [active] or closed [silent] at each stage.

但我们总是看到在每个阶段打开[活跃]或关闭[沉默]的相同区域。

We identified 280,000 genomic regions that are reproducibly open or closed during the aging process in specific cell types.

我们确定了 280,000 个基因组区域，这些区域在特定细胞类型的衰老过程中可重复地打开或关闭。

Yes, the abrupt changes in mammalian aging along with the coordinated cellular dynamics at each stage suggest there are upstream signals that control aging.

是的，哺乳动物衰老的突然变化以及每个阶段协调的细胞动力学表明存在控制衰老的上游信号。

It’s like a tree in autumn: Its leaves fall not in a linear way but in just two weeks during the transition between summer and autumn.

就像秋天的一棵树：它的叶子不是以线性方式落下，而是在夏季和秋季过渡期间的短短两周内落下。

The changes in daylight trigger the release of a signal and then the system gets changed.

日光的变化会触发信号的释放，然后系统就会发生变化。

In mammalian aging, the abrupt changes show there is some kind of signaling that drives the system.

在哺乳动物的衰老过程中，突然的变化表明存在某种信号驱动系统。

We have found both internal molecular programs — proteins that control gene expression — and external, secreted molecules called cytokines that drive the cellular changes.

我们发现了内部分子程序（控制基因表达的蛋白质）和称为细胞因子的外部分泌分子，它们驱动细胞变化。

We have identified some rare vulnerable cell types that could be targets for anti-aging interventions, and we have found the molecular code that drives the aging process, so we can develop some approaches to reprogram that code.

我们已经确定了一些罕见的脆弱细胞类型，可以作为抗衰老干预的目标，并且我们已经找到了驱动衰老过程的分子代码，因此我们可以开发一些方法来重新编程该代码。

Crucially, we have shown that the regenerative capacity and robustness of the system decrease before middle age.

至关重要的是，我们已经证明系统的再生能力和稳健性在中年之前就会下降。

So if we want to rescue aging, we should start early.

所以，如果我们想要拯救衰老，就应该尽早开始。

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《Quanta》杂志对评论进行审核，以促进知情、实质性、文明的对话。

Abusive, profane, self-promotional, misleading, incoherent or off-topic comments will be rejected.

辱骂、亵渎、自我推销、误导、语无伦次或偏离主题的评论将被拒绝。

Moderators are staffed during regular business hours (New York time) and can only accept comments written in English.

版主在正常工作时间（纽约时间）有工作人员，并且只能接受英文评论。